ADPKD and IPMN: Mere Coincidence or Double Trouble?

Abstract

This article constitutes a review of the existing literature on the potential correlation between autosomal dominant polycystic kidney disease (ADPKD) and intraductal papillary mucinous neoplasms (IPMN) of the pancreas. Additionally, it presents a clinical case where familiarity for both pathologies was observed, derived from the direct experience of our clinic, reinforcing the hypothesis of a possible common pathogenetic pathway. The review focuses on the potential genetic correlation between these two pathologies within the realm of ciliopathies, emphasizing the importance of targeted screening and monitoring strategies to detect pancreatic complications early in patients with ADPKD. Furthermore, it highlights the complexity in the clinical management of these rare conditions and underscores the importance of early diagnosis in optimizing clinical outcomes.

Keywords: ADPKD, IPMN, ciliopathies, polycystic diseases

Sorry, this entry is only available in Italian.

Introduzione

La malattia del rene policistico autosomico dominante dell’adulto (ADPKD) è la malattia renale geneticamente determinata più frequente e la quarta causa di terapia dialitica sostitutiva nel mondo. Essa è caratterizzata dallo sviluppo di molteplici cisti nei reni e in vari altri organi. Le principali caratteristiche dell’ADPKD includono l’aumento del volume renale in toto e la perdita progressiva della funzione renale [1].

La maggior parte dei casi di ADPKD è dovuta a mutazioni nei geni PKD1 e PKD2, che codificano per le proteine policistina 1 e policistina 2. Queste proteine formano un complesso recettore-canale espresso nella membrana cellulare plasmatica e nella membrana primaria delle ciglia apicali; ADPKD, pertanto, è classificata come una ciliopatia [1]. Le ciliopatie sono un gruppo di disturbi causati da difetti nella struttura o nella funzione delle ciglia. Queste condizioni derivano da mutazioni ereditarie che influenzano la formazione delle ciglia primarie e le vie di segnalazione ad esse correlate. In ADPKD lesioni cistiche possono formarsi in altri distretti come il fegato, la milza e il pancreas [24].

La severità di espressione della malattia correla con il tipo di mutazione genetica. I pazienti con mutazioni sul gene PKD2 generalmente presentano una forma più lieve di malattia renale rispetto a quelli con mutazioni sul gene PKD1, in particolare rispetto ai portatori delle cosiddette mutazioni PKD1 troncanti [5]. 

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Alström syndrome, a rare cause of renal failure: case report and review of the literature

Abstract

We describe the case of a 26-year-old male patient with a previous diagnosis of Alström Syndrome who presented drowsiness, dyspnea, tremors, and a dull abdominal pain, without signs of peritoneal irritation. The patient also presented sensorineural hearing loss, decreased vision, due to chorioretinal dystrophy, difficulty walking with back-lumbar double curve scoliosis, impaired glycemic homeostasis, and a significant deterioration of renal function.

Alström syndrome is a multisystem disease characterized by rod-cone dystrophy, hearing loss, obesity, insulin resistance and hyperinsulinemia, type 2 diabetes mellitus, dilated cardiomyopathy, and progressive renal and hepatic dysfunction. Around 450 cases have been identified worldwide. Clinical signs, age of onset and severity can vary significantly between different families and within the same family.

Careful nephrological follow-up is necessary in patients with syndromic ciliopathies, since long-term kidney problems can have an impact on other diseases, eg. cardiovascular disease.

Keywords: rare diseases, ciliopathies, chronic kidney failure

Sorry, this entry is only available in Italian.

Introduzione

La sindrome di Alström, descritta per la prima volta nel 1959, è una malattia multisistemica caratterizzata da distrofia dei coni-bastoncelli, perdita dell’udito, obesità, resistenza all’insulina e iperinsulinemia, diabete mellito tipo 2, cardiomiopatia dilatativa (CMD), disfunzione renale ed epatica progressiva. A livello mondiale sono stati diagnosticati circa 450 casi. I segni clinici, l’età di esordio e la gravità possono variare significativamente tra le diverse famiglie e all’interno della stessa famiglia.

 

Descrizione del caso clinico

Il paziente è un maschio di 26 anni affetto Sindrome di Alström esordita in età neonatale. Il paziente è primogenito, nato a termine da parto spontaneo dopo una gravidanza normocondotta. Dall’età di 2 mesi il bambino presentava sonnolenza in ambiente luminoso. All’età di 4 mesi praticava una visita ambulatoriale presso l’Ospedale Pediatrico Regionale dove veniva riscontrato un accorciamento del muscolo sternocleidomastoideo destro, per cui veniva prescritta immobilizzazione del rachide cervicale in flessione per 1 mese; una visita oculistica riscontrava refrazione ipermetropica e nistagmo bilaterale. Effettuava poi una visita neurologica per approfondimento diagnostico, con PEV e EEG nella norma. A 20 mesi, insorgeva fotofobia e si effettuava una PEV di controllo che evidenziava un ritardo di conduzione troncoencefalica. Successivamente, a 8 anni, venivano diagnosticate l’insufficienza renale, il diabete iperinsulinemico e la sordità neurosensoriale. All’età di 10 anni la diagnosi di Sindrome di Alström veniva confermata dall’analisi molecolare del gene ALMS1 (omozigosi per la mutazione C11460G nell’esone 16).

I suoi genitori sono sani ed ha un fratello affetto anch’egli da Sindrome di Alström. Nel corso degli anni il paziente, seguito presso il centro di riferimento regionale per le malattie rare, ha effettuato regolari visite di controllo (visita oculistica, cardiologica, endocrinologica, dermatologica, neuropsichiatrica e nefrologica) e controlli strumentali (ecografia addome ed ecocardiogramma). Tale monitoraggio era finalizzato al controllo delle varie manifestazioni della Sindrome. Infatti, il paziente presentava ipoacusia neurosensoriale, diminuzione del visus da distrofia corioretinica, difficoltà di deambulazione con scoliosi a doppia curva dorso-lombare ed alterazione dell’omeostasi glicemica.

Giungeva alla nostra osservazione per comparsa di stato soporoso, dispnea, tremori e dolore addominale sordo senza segni di irritazione peritoneale. Da due giorni era in trattamento con ceftriaxone 1 gr/die per riferita bronchite con febbre. All’ingresso in ospedale i suoi parametri erano: SpO2 97%, P.A. 130/70 mmHg, polsi isosfigmici. L’esame obiettivo evidenziava addome poco trattabile e, al torace, mv aspro con crepitii consensuali. Gli esami di laboratorio erano: Azotemia 309 mg/dl; Creatininemia 22,8 mg/dl; Glicemia 184 mg/dl; Sodio 132 mEq/l; Potassio 5.0 mEq/L; Calcemia 8,6 mg/dl; Fosforemia 11.0 mg/dl; Amilasi 927 UI/L; Lipasi 4306 UI/L; CK-MB(massa) 6,2 ng/ml; Troponina I 0,10 ng/ml; Colesterolo totale 122 mg/dl; Trigliceridi 210 mg/dl; G.B. 27400/mmc; G.R. 4210000/mmc; HGB 11,1 gr/dl; HCT 34,3 %; PLT 207000/mmc. L’emogasanalisi arteriosa mostrava acidosi metabolica con eccesso di basi -19,8 mmol/L.

Il nefrologo chiamato in consulenza urgente dava indicazione al trattamento dialitico immediato tramite incannulamento ecoguidato della vena femorale sinistra con catetere bilume 11.5 Fr/Ch (3.8 mm) x 19.5 cm. Durante il ricovero venivano praticati ulteriori esami ematochimici, ecografia addominale, emogasanalisi, TC encefalo, TC torace e addome, e colangio- RM. L’ecografia renale evidenziava: reni bilateralmente ai limiti bassi per volumetria (D.L. dx 7,5 cm, D.L. sin 8 cm), ridotto spessore parenchimale ed iperecogenicità corticale. Inoltre, è stato effettuato l’ecocardiogramma per valutare la possibilità di una cardiomiopatia dilatativa e tale esame ha dato esito negativo. Tali ulteriori indagini e l’anamnesi patologica remota ci hanno orientato per una cronicità della insufficienza renale; pertanto il paziente è stato immesso in un programma di dialisi cronica. I trattamenti emodialitici sono stati effettuati con dializzatore in polietersulfone Revaclear 300 avente superficie di 1,4 mq. Dopo il secondo trattamento emodialitico si assisteva ad un drastico miglioramento del sensorio. Come riportato in letteratura anche il caso osservato presentava inoltre pancreatite acuta associata, con riscontro di alterazioni della crasi lipidica (ipertrigliceridemia) e con aspetto TAC caratteristico (Fig. 1).

Figura 1: Aspetto tumefatto della coda del pancreas ed imbibizione della fascia pararenale anteriore di sinistra
Figura 1: Aspetto tumefatto della coda del pancreas ed imbibizione della fascia pararenale anteriore di sinistra

Le pancreatiti in questi pazienti possono essere pericolose per la vita. È stato inoltre esclusa una genesi litiasica. Gli esami colturali e di laboratorio hanno escluso una sepsi con disfunzione multi organo. Il trattamento della pancreatite, con digiuno ed idratazione, nonché il trattamento sostitutivo della funzione renale, hanno permesso la risoluzione della pancreatite ed un sostanziale miglioramento dell’outcome del paziente.

 

Discussione

La sindrome di Alström è una rara sindrome autosomica recessiva ereditaria causata da una mutazione in entrambe le copie del gene ALMS1 localizzato sul cromosoma 2 (regione 2p13.1) e comprendente 23 esoni [2]. La proteina ALMS1 è un componente del centrosoma alla base delle ciglia;risulta formata da 4169 Aa e partecipa all’assemblaggio del materiale pericentriorale (Fig. 2). Sebbene l’esatta funzione biologica di ALMS1 rimanga oscura, l’evidenza attuale suggerisce che le funzioni includono il mantenimento della funzione ciliare, la modulazione del trasporto intracellulare e la differenziazione degli adipociti. Nel modello murino della sindrome, con proteina ALMS1 anomala, si evidenzia una perdita di ciglia nelle cellule tubulari prossimali mentre nei fotorecettori si ha accumulo di vescicole intracellulari [3].

Le mutazioni di geni che codificano per proteine del Ciglio Primario sono alla base di patologie definite ciliopatie. Le ciglia primarie sono organelli sensoriali che si trovano su molte cellule dell’uomo e svolgono ruoli critici nella comunicazione cellulare relativamente alla proliferazione e differenziazione, motilità e polarità cellulare [4]. Trattasi di un eterogeneo gruppo di disordini che interessano molteplici organi, compreso il rene. La malattia del rene policistico autosomico dominante (ADPKD) “rappresenta la ciliopatia più comune, e si presenta con caratteristiche cliniche uniche, specifiche. Ad essa si aggiungono la malattia del rene policistico autosomica recessiva (ARPKD), la nefronoftisi (NPHP), ed un gruppo di ciliopatie sindromiche caratterizzate da difetti renali ed extra-renali, come la distrofia retinica, il situs inversus, disturbi cognitivi e obesità. Tra queste ultime si annoverano la sindrome di Bardet-Biedl (BBS), la sindrome di Senior-Löken (SNLS), la sindrome di Meckel (MKS), la sindrome di Joubert (JBTS), la sindrome oro-facio-digitale di tipo 1 (OFD1), la distrofia toracica asfissiante di Jeune (JATD) e la sindrome di Alström (ALMS)” [5].

Struttura del cilio primario
Figura 2: Struttura del cilio primario. L’assonema è composto da nove paia di microtubuli ed è ancorato alla cellula mediante il corpo basale che è un centriolo modificato, costituito da nove triplette di microtubuli. Il centriolo madre gioca un ruolo chiave nella ciliogenesi, reclutando le molecole necessarie per l’allungamento degli assonemi. Il centriolo figlio risulta dalla duplicazione del centriolo madre durante la fase S della mitosi. Le frecce indicano gli elementi chiave del ciglio strutturale (l’assonema, la zona di transizione e corpo basale) e le proteine coinvolte nelle ciliopatie renali e nel carcinoma a cellule renali (RCC) (tradotto da Adamiok-Ostrowska) [3]
La sindrome è caratterizzata dall’insorgenza di obesità nell’infanzia o nell’adolescenza, diabete di tipo 2, spesso con grave insulino-resistenza, dislipidemia, ipertensione e grave fibrosi multiorgano che coinvolge fegato, reni e cuore. La sindrome di Alström è anche caratterizzata da una progressiva perdita della vista e dell’udito, una forma di malattia cardiaca che indebolisce il muscolo cardiaco (cardiomiopatia dilatativa) e bassa statura. Questo disturbo può anche causare problemi medici gravi o potenzialmente letali che coinvolgono fegato, reni, vescica e polmoni. Le manifestazioni cliniche della sindrome di Alström variano in gravità e non tutti gli individui affetti hanno tutte le caratteristiche associate al disturbo [1].

Le manifestazioni di danno renale si rendono evidenti soprattutto dopo la seconda-terza decade di vita e comprendono: diminuzione della capacità di concentrazione delle urine, ipertensione, acidosi tubulare renale, nefrocalcinosi disfunzione del tratto urinario inferiore, infezioni intercorrenti, reflusso vescico-ureterale e instabilità del detrusore [6]. Insufficienza renale terminale si verifica nel 50% dei pazienti Le cause dell’insufficienza Renale sono la fibrosi e l’’atrofia tubulare. Le  infiltrazioni fibrotiche sono alla base degli altri fenotipi clinici, in particolare cardiaco, polmonare ed epatico suggerendo meccanismi patogeni comuni [7]. Non c’è correlazione con il diabete o con la pielonefrite [8] in quanto sono assenti le caratteristiche istopatologiche della nefropatia diabetica e/o da reflusso suggerendo che la malattia renale possa essere la manifestazione primaria della sindrome anche se non si può escludere un effetto additivo sulla progressione del danno renale da parte del diabete e dell’ipertensione [9].

Prima della scoperta delle mutazioni ALMS1, la diagnosi di Sindrome di Alström era basata unicamente sul fenotipo, ma esso è molto variabile anche all’interno dei nuclei familiari. Pertanto, sono stati proposti criteri diagnostici specifici per età riportati in Tabella I [1012].

Criteri diagnostici di sindrome di Almstrom tradotto da Jan D Marshall 2007
Tabella I: Criteri diagnostici di sindrome di Almstrom tradotto da Jan D Marshall 2007 [10]
Tali criteri sono fondamentali per la diagnosi di sindrome di Almstrom, la cui diagnosi differenziale con altre patologie può essere complessa. Citiamo in particolare la Sindrome di Bartdet-Bieldl, che presenta molte analogie cliniche con la sindrome di Almstrom, dalla quale tuttavia si differenzia per la polidattilia e per la più bassa prevalenza di cardiomiopatia dilatativa nella BBS rispetto alla AS. oltre che per una diversa diagnosi molecolare [13].

 

Conclusioni

La sindrome di Alström è una rarissima malattia causa di insufficienza renale terminale necessitante di terapia dialitica. I pazienti raramente sopravvivono oltre i 40 anni. Al momento non c’è alcun trattamento specifico, ma diagnosi e interventi precoci possono rallentare la progressione delle espressioni fenotipiche migliorando il periodo di sopravvivenza e la qualità della vita dei pazienti.

 

Bibliografia

  1. Wu WC, Chen SC, Dia CY, Yu ML, Hsieh MY, Lin ZY, Wang LY, Tsai JF, Chang WY, Chuang WL. Alström syndrome with acute pancreatitis: a case report. Kaohsiung J Med Sci. 2003; 19(7):358-61. https://doi.org/10.1016/S1607-551X(09)70438-3
  2. Tahani N, Maffei P, Dollfus H, Paisey R, Valverde D, Milan G, et al. Consensus clinical management guidelines for Alström syndrome. Orphanet J Rare Dis 2020; 15(1):253. https://doi.org/10.1186/s13023-020-01468-8
  3. Adamiok-Ostrowska A, Piekiełko-Witkowska A. Ciliary Genes in Renal Cystic Diseases Cells 2020; 9(4):907. https://doi.org/10.3390/cells9040907
  4. Dillman JR, Trout AT, Smith EA, Towbin AJ. Hereditary Renal Cystic Disorders: Imaging of the Kidneys and Beyond. Radiographics 2017; 37:924-46. https://doi.org/10.1148/rg.2017160148
  5. Cervesato A, Raucci R, Buononato D, Marchese E, Capolongo G, et al. La proteomica e la metabolomica nello studio delle malattie genetiche del rene: dai big data alla medicina di precisione. G Ital Nefrol 2020; 37(6):n5. https://giornaleitalianodinefrologia.it/2020/11/37-06-2020-05/
  6. Marshall JD, Maffei P, Collin GB, Naggert JK. Alström Syndrome: Genetics and Clinical Overview. Curr Genomics 2011; 12:225-35. https://doi.org/10.2174/138920211795677912
  7. Izzi C, Maffei P, Milan G, Tardanico R, Foini P, Marshall J, Marega A, Scolari F. The Case ∣ Familial occurrence of retinitis pigmentosa, deafness, and nephropathy. Kidney Int 2011; 79(6):691-2. https://doi.org/10.1038/ki.2010.514
  8. Medical Handbook. https://www.Alström.org.uk
  9. Baig S, Paisey R, Dawson C, Barrett T, Maffei P, Hodson J, Rambhatla SB, Chauhan P, Bolton S, Dassie F, Francomano C, Marshall RP, Belal M, Skordilis K, Hayer M, Price AM, Cramb R, Edwards N, Steeds RP, Geberhiwot T. Defining renal phenotype in Alström syndrome. Nephrol Dial Transplant 2020; 35(6):994-1001. https://doi.org/10.1093/ndt/gfy293
  10. Marshall JD, Beck S, Maffei P, Naggert JK. Alström syndrome. Eur J Hum Genet 2007; 15(12):1193-202. https://doi.org/10.1038/sj.ejhg.5201933
  11. Hearn T. ALMS1 and Alström syndrome: a recessive form of metabolic, neurosensory and cardiac deficits. J Mol Med (Berl) 2019; 97(1):1-17. https://doi.org/10.1007/s00109-018-1714-x
  12. Jaykumar AB, Caceres PS, King-Medina KN, Liao TD, Datta I, Maskey D, Naggert JK, Mendez M, Beierwaltes WH, Ortiz PA. Role of Alström syndrome 1 in the regulation of blood pressure and renal function. JCI Insight 2018; 3(21):e95076. https://doi.org/10.1172/jci.insight.95076
  13. Brühl P, Schwanitz G, Mallmann R, Müller SC, Raff R. Bardet-Biedl-Syndrom: nephrourologische und humangenetische Aspekte [Bardet-Biedl syndrome: aspects of nephro-urology and human genetics]. Klin Padiatr 2001; 213(1):8-12. German. https://doi.org/10.1055/s-2001-1126

The renal lesions in Bardet-Biedl Syndrome: history before and after the discovery of BBS genes

Abstract

Various renal lesions of the Bardet-Biedl syndrome (BBS) have been described, including macroscopic and microscopic kidney abnormalities, polyuria, polydipsia and chronic renal failure. However, these renal symptoms were completely overlooked for about fifty years after the first description of the syndrome. The observation of a familial origin of the syndrome began in 1753, with Maupertuis and Réaumur describing hereditary forms of polydactyly. In the early 19th century, Martin mentioned an inherited case of blindness. Subsequently, von Graefe (1858) reported on a familial occurrence of both of blindness and deafness. The introduction of the ophthalmoscope by von Helmholtz (1851) allowed for the identification of patients with retinal degeneration. Systematically using this instrument, Laurence and Moon (1866) were the first to describe a familial case of retinal degeneration combined with obesity and cognitive impairment. Due to the influential work of Froehlich, Cushing, and Babinski, attention then shifted to obesity. The syndrome was definitively identified by 1920 through Bardet’s observations familial cases of obesity, blindness, polydactyly, and hypogonadism. Biedl in 1922 observed further cases of the syndrome. In recognition of this history, the disease was named Laurence-Moon-Bardet-Biedl Syndrome. The renal anomalies were not described until fifty years later, in 1977. In 1993, the quest for the genes involved in BBS began with the isolation of 21 different genes. In 2003 two concepts emerged: the existence of a spectrum of ‘ciliopathies’ and the concept of the BBSome. Afterwards, the gene-phenotype relationship was researched using transgenic mice.

Keywords: ciliopathies, hereditary, obesity, retinitis, chronic kidney disease

INTRODUCTION

According to the influential theory of Thomas Kuhn (1922-1996) (1), most scientists work constrained by current influential paradigm and are devoted to solving small problems (‘puzzle-solving’). The dominant paradigm is important for the interpretation of the data, but it may blind scientists to new phenomena not considered part of the paradigm. One example of this theory comes from the field of nephrology, where the pivotal renal anomalies in Bardet-Biedl Syndrome went completely unnoticed for more than 50 years after the discovery of the syndrome. Tus, the BBS syndrome is an example of how an essential clinical element may go unnoticed for a long time and is evaluated only after a shift in the attention of the scientific community (specifically, the introduction of renal biopsy and immunofluorescence).

The Bardet-Biedl Syndrome (BBS) is a rare genetic disorder characterized by retinal degeneration, polydactyly, obesity, learning disabilities, hypogonadism and renal anomalies. Various renal lesions of BBS have been described including (i) fetal lobulation (ii) calyceal clubbing, (iii) focal sclerosing glomerulonephritis, (iv) interstitial nephritis, and (v) changes in the glomerular basement membrane. Polyuria, polydipsia and chronic renal failure have been also reported in many case reports (2). Although the renal anomalies are today one of the primary features of the disease, it took almost 50 years after the description of the syndrome for renal symptomatology to be included.

Here we will review the observations that drew the attention of Bardet and Biedl to the disease and why the renal features were not observed. Afterwards, we will focus on the role that the identification of BBS genes played in changing our perception of the disease and its renal lesions. A timetable of the discoveries is summarized in Table 1.

 

HOW THE SYNDROME WAS DISCOVERED

The identification of BBS required the evolution of the following concepts: 1) the existence of hereditary forms of blindness and polydactyly, which fostered the search for combined hereditary forms of more complex diseases 2) the invention of the ophthalmoscope, which allowed scientists to identify and classify retinal degeneration and 3) a paradigm-shift concerning the nature of obesity, which focused attention on hereditary forms of obesity (such as BBS), but also served as a blinder impeding the identification of other features such as kidney failure.

The observation of a familial origin of the syndrome began in 1753, with Maupertuis and Réaumur (Figure 1, Figure 2) describing hereditary polydactyly. While polydactyly was widely known since ancient times, the hereditary aspect of the malformation gained notice in the late 1700s. Pierre-Louis Moreau de Maupertuis, (born Sept. 28, 1698, Saint-Malo, France—died July 27, 1759, Basel, Switz.), was a mathematician and astronomer who popularized Newton’s theories (3). In Système de la nature ou Essai sur les corps organisés (1751) he studied the transmission of polydactyly in four generations of a Berlin family, providing the first report of the trait as hereditary (4). Renè-Antoine Ferchault de Réaumur (1683-1757), the famous French scientist who gave his name to the temperature scale, is reported by Huxley (1894-1963) (5) to have analyzed data from three families (named Kelleia) from Malta with hereditary polydactyly. Similar to polydactyly, progressive blindness was also known since ancient times; however, the possibility of a hereditary form of blindness was first noted in the early 19th century by Martin. He reported, in the Baltimore Medical and Physical Recorder (1809), on the Lecomptes, a Maryland family of French origin whose members suffered progressive blindness (5). While none of these authors were describing actual cases of BBS, their work did refocus subsequent researchers on hereditary forms of polydactyly and blindness.

Indeed, soon after, Albrecht von Graefe (1828-1870) (6) and thereafter Liebreich first reported a hereditary combination of blindness and deafness in cases of what would be called retinitis pigmentosa, furthering the concept of combined forms of hereditary traits, and these observations are, in fact, cited by Laurence and Moon in their work (see below). Another essential discovery that must be acknowledged for the history of BBS was the invention of the ophthalmoscope in 1851 by Hermann von Helmholtz (1821-1894), which allowed the observation of the retina and hence the definition of retinitis pigmentosa (Figure 3). The use of the new device, the ophthalmoscope, was hence promoted in England by John Zachariah Laurence (1829-1870), a surgeon and ophthalmologist at the ophthalmologic hospital in Southwark (Figure 4). In 1866, together with his colleague Robert Charles Moon (1844-1914) (Figure 5), a house surgeon at the same hospital (who then moved in Philadelphia), they were the first to describe, using the ophthalmoscope, a familial case of combined retinal degeneration, obesity, and cognitive impairment (7).

In the first years of the 20th century, medical attention shifted to hypothalamic forms of obesity-hypogonadism thanks to the work of a neurologist, Joseph Babinski (1857-1932), a pharmacologist, Alfred Fröhlich (1871-1953) (8) and a neurosurgeon, Harvey Cushing (1869-1939) (9). Again, in the history of science, we see how important advances in one field may come through collaborations with other fields, and how this chance partnership was a necessary step in fully defining BBS. Fröhlich’s strong influence is visible when the first report of a BBS case was attributed to a pituitary malfunction.

Around this period a certain number of observations of obesity, polydactyly and retinitis pigmentosa are reported by several authors: in 1887 Ferdinand-Jean Darier (1856-1938) reports the association of retinitis pigmentosa and polydactyly (10). In 1989 Elie von Cyon (also known as de Cyon, 1843-1912) presents the case of a 12-year old boy with obesity, growth and mental retardation, and hereditary polydactyly (11). In 1898 Ed Fournier reports retinitis pigmentosa and syndactyly (12). In 1913 Rozabel Farnes reports adipose-genital syndrome with polydactyly (13). In 1914 an Italian radiologist working in Naples, Mario Bertolotti (1876-1957) presented the case of Marguerite Catt, 39 years old, with polydactyly, mental retardation, obesity, retinitis pigmentosa, and hypogonadism (14). In 1918 J Madigan and Thomas Verner Moore (1877-1969) described a case of mental retardation, obesity, hypogonadism, retinitis pigmentosa, and tapering toes (15).
Finally, in 1920 a French medical student, George Louise Bardet (1885-1966), in his medical degree thesis, collected all these cases and his own observation of a familial case of obesity, hexadactyly, retinitis pigmentosa and hypogonadism and proposed the existence of a triad (13). He discussed this finding using the current paradigm of hypophyseal/hypothalamic obesity: “Two congenital malformations (hexadactyly and retinitis pigmentosa) in a child who became obese from birth. What is the gland which can be incriminated? (…) We believe this case must be attached to a very special clinical variety of hypophysis obesity”. Bardet’s triad (obesity, polydactyly, retinitis pigmentosa) gained success after the father of modern endocrinology, Arthur Biedl (1869-1933), in 1922 observed further cases of the syndrome. Biedl named the syndrome adipose-genital dystrophy and thought it was of cerebral origin, in line with the paradigms of that period (Figure 6). In recognition of this history, the disease was named Laurence-Moon-Bardet-Biedl Syndrome. Later, thanks to the work of Ammann in 1970 and Schachat and Maumenee in 1982, Laurence-Moon and Bardet-Biedl Syndromes came to be considered two different entities and possibly part of the same disease spectrum. In the first half of 1900, BBS was officially defined, but none of these authors noticed abnormalities in kidney function, which is today acknowledged as an important signature of the syndrome.
Why then were the renal features of the syndrome missed for almost 50 years? It is tempting to see this as an example of Kuhn’s hypothesis that scientists work on ‘puzzle-solving’ within an influential paradigm. The paradigm of that period was hypothalamic obesity, whereas kidney failure was not considered. Scientists observing new cases of BBS focused on obesity and dismissed other possible features of the disease.
It is intriguing that, even in 1995, in the excellent editorial by George Bray (born 1931) on the syndrome in Obesity Research, kidney dysfunction is completely ignored by the author (16).

 

THE RENAL LESIONS BEFORE BBS GENES

Awareness of the renal involvement in BBS starts in the late 1960s with the work of McLoughlin and Shanklin (17), Nadjmi (18), Hurley (19) and Falkner (20). McLoughlin and Shanklin (17), Nadjmi et al. (18) first reviewed necropsies of BBS from the literature and found a high incidence of renal/genitourinary malformations; Nadjmi further observed that most of cases reported in the literature since 1940 died for uremia and therefore renal failure was a major cause of early death in BBS patients. According to Nadjmi, the first autopsy reporting a BBS subject passed due to uremia was by Radner in 1940 (Acta Med Scand 105:141); however, genitourinary tract malformations were already observed since 1938 by Griffiths (J Neurol Psychiat 1:1-6), and Riggs (Arch Neurol Psychiat 39:1041). It is possible that the systematic renal involvement in BBS was missed before because the histologic classification of kidney diseases reached its maturity only when kidney biopsy and the kidney immunofluorescence have been available around 1950, thus driving attention to this organ.

The diffusion of the technique of percutaneous kidney biopsy by Nils Alwall (1904-1986) allowed Hurley et al (19) to first report histological data from a series of nine BBS children (Figure 7 A-B). The results were quite variable, from mesangial proliferation to sclerosis, cystic dilatation of the tubules, cortical and medullary cysts, periglomerular and interstitial fibrosis, chronic inflammation.

Falkner et al. (20) found in a 24-month old child with BBS right sided vesical-ureteral reflux, cystocele, urinary tract infections, growth arrest of the right kidney. They also confirm the mesangial hypercellularity by percutaneous biopsy (Figure 7 C).

In 1990 the incidence of renal abnormalities in BBS was finally determined to be very high: up to 90% of the patients, and therefore become a new signature of the syndrome, more than 50 years from its initial definition (2). In the meanwhile, the spectrum of renal abnormalities was stably defined as:

Functional: polyuria, polydipsia, aminoaciduria, reduction of maximum concentrating capacity, chronic renal failure, hypertension

Macroscopic: fetal lobulation, cystic dysplasia and calyceal cysts, small kidneys, calyceal clubbing or blunting

Microscopic: swelling of endothelial cells, tubular and interstitial nephritis with glomerulosclerosis.

In conclusion, we believe that the attention to the nephrological character of the BBS was finally reached only when (i) technical advancements were available (that is the invention of the percutaneous biopsy) and (ii) when a general attention of the medical entourage was driven towards the kidney function: we should remind that in 1943 Willem Johan Kolff (1911 – 2009) first built a dialyzer machine, further developed by Nils Alwall. At the end of 60’ nephrology was a mature science and the greater awareness towards uremia led to a revision of syndromic diseases.

However, the condition remained largely unclear even after the discovery of the renal abnormalities: major advances in a new behind the complex trait was the discovery of the gene defects causing BBS.

 

THE RENAL LESIONS AFTER BBS GENES

The quest for the genes occurred in two phases: from 1993 to 2000 a genetic mapping was pursued, with the identification of several DNA loci involved in the disease. In 2000 the identification of the first BBS gene (now they number 21), MKKS, based on the similarity between the BBS and the McKusick-Kaufman syndrome (MKS), occurred (21). In 2003 Ansley et al demonstrated that mammalian BBS8 gene was restricted to ciliated cells (21). This finding raised the hypothesis that BBS proteins play a role in cilia function. Meanwhile, other genes of the same family were found to cause BBS, with at least 17 different genes implicated up to now.

The field was quite mature at the time because a second, more common condition, was already found to involve cilia: the polycystic kidney disease (PKD). This is also a hereditary condition and followed almost the same path of BBS (anatomical period-genetic period-functional period), which ultimately led to the paradigm of the involvement of cilia dysfunction in the genesis of the disease.

It should be stressed that, again, the major advancement in the paradigm did not come directly from the studies on the disease, but from studies on flagellated protozoa: it was a genetic study on immobile forms of these protozoa which led to the identification of this gene. When the same was found to be involved in PKD and then in other diseases such as BBS, it was almost immediate the formation of a new paradigm of ‘ciliopathies’. All genes involved in these genetic diseases and in the cilium were then functionally grouped in a multiprotein complex called BBSome.

After the period of discovery of BBS genes and the construction of the concept of the BBSome, some new insights in the renal pathology of BBS have been addressed. First, the gene-phenotype relationship has been studied in much detail, with a categorization of mutations leading to various associations of the visual, metabolic and kidney phenotypes (23, 24). Second, a number of transgenic mice are now available for testing of pathogenic hypotheses and new pharmacological approaches. Risk factors for the development of the renal disease have been studied in large cohorts (22 – 24), and the usefulness of renal transplantation has been demonstrated in a separate study (25, 26). A contribution for low protein diet in the preservation of renal function in BBS has also been reported (27). Finally, a study from one of us (28, 29) showed combined impaired water handling in BBS.

These functional changes in BBS kidney might be mediated, at least in part, by mistrafficking of apical membrane proteins, leading to tubular dysfunction (41). In turn, this might be related to the renal hyposthenuria in BBS, that has been recognized as the most common renal dysfunction in the absence of renal insufficiency (42, 43).

 

Acknowledgments

I am indebted with dr. David Widmer, who critically reviewed the manuscript, with useful suggestions and critiques.

 

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