An infant with polydactyly and renal anomalies: early diagnosis of a rare syndrome

(Section Editor: K. Kühn)

Daniella Magen, Nathan Ish-Shalom1, Abraham Lorber2, Asaad Khoury2 and Israel Zelikovic

Pediatric Nephrology Unit and 2 Pediatric Cardiology Unit, Rambam Medical Center, and 1 Department of Pediatrics, Carmel Medical Center, Faculty of Medicine, Technion–Israel Institute of Technology, Haifa, Israel

Keywords: Bardet–Biedl syndrome; Laurence–Moon– Biedl syndrome; non-allelic heterogeneity; pigmentary retinopathy; postaxial polydactyly

Case

A 3-week-old male infant was referred for evaluation of multiple congenital anomalies and failure to thrive. He is the fourth offspring of first degree cousins of Arab–Muslim origin. Family history was notable for obesity, learning difficulties, reduced kidney function and visual impairment in a 10-year-old brother. The infant, weighing 3.3 kg, was born after an uneventful pregnancy at full term by spontaneous delivery. On admission he appeared malnourished and weighed 3.1 kg. No facial dysmorphism was present (Figure 1). There was postaxial polydactyly of all four limbs (Figures 2 and 3). Tachypnea and dyspnea were noted, and a grade 3/6 systolic heart murmur was heard over the entire precordium. Blood pressure was normal in all four extremities. Examination of the external genitalia revealed micropenis (Figure 4) and palpable testicles of normal size. Ophthalmologic evaluation including fundoscopy was unremarkable.



View larger version (107K):
[in this window]
[in a new window]
 
Fig. 1.  General appearance of the infant. Subcutaneous fat tissue is sparse. No facial dysmorphism is seen.

 


View larger version (150K):
[in this window]
[in a new window]
 
Fig. 2.  Postaxial polydactyly of both hands.

 


View larger version (121K):
[in this window]
[in a new window]
 
Fig. 3.  Postaxial polydactyly of both feet, with partial syndacyly of the 2nd and 3rd toes of the right foot.

 


View larger version (116K):
[in this window]
[in a new window]
 
Fig. 4.  External genitalia with micropenis.

 
Serum blood urea nitrogen and creatinine levels were elevated (40 and 0.9 mg/dl, respectively). Other blood chemistries were unremarkable.

Chest X-ray showed cardiomegaly. Echocardiography revealed both atrial and ventricular septal defects, a hypoplastic aortic arch and a tubular aortic coarctation. Abdominal sonogram revealed left renal crossed ectopy (Figure 5). Both kidneys were small for age, hyperechogenic, and showed no corticomedullary differentiation. Brain ultrasonography was unremarkable.



View larger version (102K):
[in this window]
[in a new window]
 
Fig. 5.  Renal sonogram showing left renal crossed ectopy, with both kidneys located in the right abdomen. The kidneys are small for age (length 4 cm) and hyperechogenic; mild pelvic dilatation is seen.

 
The combination of postaxial polydactyly and renal, cardiac and genital malformations in an offspring of consanguineous parents, in conjunction with a sibling suffering from obesity, renal failure, mental retardation and visual impairment, have led us to diagnose Bardet–Biedl syndrome (BBS) in this young infant.

Discussion

BBS is a rare autosomal recessive disorder, characterized by obesity, pigmentary retinopathy, mental retardation, hypogenitalism, postaxial polydactyly and renal malformations. Other common manifestations include cardiac malformations, hypertension and diabetes mellitus.

The syndrome was independently described by Bardet and Biedl in the 1920s [1,2]. It was later erroneously coupled with another disorder described by Laurence and Moon, and was consequently referred to as Laurence–Moon–Biedl syndrome. Based on differences in clinical characteristics, BBS and Laurence–Moon syndrome are now recognized as separate disorders [3].

The prevalence of BBS, generally considered a rare disorder, is 1 : 160 000 in Europe. However, its prevalence is markedly increased in highly consanguineous Arab-Bedouin communities in the Middle East (1 : 13 500), and in Newfoundland, Canada [4].

There is considerable heterogeneity and intrafamilial variation in the extent and severity of clinical manifestations of BBS. Obesity, mainly of the trunk and proximal limbs, is one of the most common features. It develops in early childhood and is aggravated with age. Ocular manifestations are also common and become apparent between the ages of 4 and 10 years. They include retinal dystrophic changes leading to abnormal electroretinogram, decreased night vision, reduced visual acuity and blindness at a young age. Mild to moderate mental retardation is an additional feature of the syndrome. The frequency of mental retardation and its severity vary between reports. Hypogonadism in affected males is common. Most affected men have small external genitalia with primary testicular failure. In females, however, hypogonadism is less frequent, and normal fertility has been reported. Dysmorphism of extremities, including postaxial polydactyly, syndactyly or brachydactyly, is one of the earliest and most common manifestations of BBS. Renal involvement is observed in most affected individuals. It consists of structural and functional abnormalities such as calyceal or pelvic dilatation, fetal lobulation, and focal and diffuse cortical loss, as well as tubular dysfunction, hypertension and progressive renal failure [5,6]. Cardiac anomalies in BBS include various valvular malformations, thickening or defects of the interventricular septum, and hypertrophic cardiomyopathy [7]. The prognosis of patients with BBS is generally poor. Their survival and quality of life depend on the severity of clinical features, as well as on the quality of the medical care they receive [8].

BBS is an autosomal recessive disorder characterized by non-allelic heterogeneity. Genetic analysis has mapped the disease to several independent loci, all of which produce similar phenotypes. Linkage analysis studies have so far identified six distinct loci responsible for the syndrome (BBS types 1 to 6, mapped to chromosomes 11q13, 16q21, 3p, 15q22.2-q23, 2q31 and 20p12, respectively) [4,9]. To date, only three of the six possible genes mutated in BBS have been identified, including: BBS2, which encodes a protein of unknown function; BBS4, which encodes a protein with homology to O-linked N-acetyl glucosamine transferase; and BBS6, which encodes a putative chaperone protein [10]. The remaining three BBS genes, as well as the biological functions of the BBS gene products responsible for the disorder, remain to be identified. It has been suggested that identification of the molecular and biochemical pathways involved in the pathogenesis of BBS may provide clues to the mechanisms underlying common disorders such as obesity, diabetes mellitus and mental retardation [10,11].

Most cases of BBS are diagnosed after the first decade of life [5]. Diagnosis in early infancy is very rare. Delay in diagnosis is probably related to the slow evolving nature of clinical features in this syndrome. In our case, the constellation of clinical findings in both infant and older sibling, combined with the family history of consanguinity has led to the diagnosis of BBS in the neonatal period. Early diagnosis of BBS may significantly improve the quality of medical care provided to patients with this syndrome and may increase their survival.

Teaching points

BBS is a rare genetic disorder, inherited as an autosomal recessive trait. Since in most cases the full-blown clinical picture does not evolve before the end of the first decade of life, diagnosis of the syndrome during early infancy is very rare. Nevertheless, this case illustrates that thorough clinical evaluation coupled with awareness of this rare syndrome can lead to the diagnosis of BBS in early life.

Notes

Correspondence and offprint requests to: Daniella Magen, MD, Pediatric Nephrology Unit, Rambam Medical Center, PO Box 9602, Haifa 31096, Israel. Email: d_magen{at}rambam.health.gov.il Back

References

  1. Bardet G. Sur un syndrome d'obésité infantile avec polydactylie et rétinite pigmentaire (contribution à l'étude des formes cliniques de l'obésité hypophysaire). Thesis, University of Paris, France, 1920
  2. Biedl A. Ein Geschwisterpaar mit adiposo-genitaler Dystrophie. Dtsch Med Wochenschr1922; 48: 1630
  3. Schachat AP, Maumenee IH. The Bardet–Biedl syndrome and related disorders. Arch Ophthal1982; 100: 285–288[Abstract]
  4. Woods MO, Young TL, Parfrey PS, Hefferton D, Green JS, Davidson WS. Genetic heterogeneity of Bardet–Biedl syndrome in a distinct Canadian population: evidence for a fifth locus. Genomics1999; 55: 2–9[ISI][Medline]
  5. Beales PL, Elcioglu N, Woolf AS, Parker D, Flinter FA. New criteria for improved diagnosis of Bardet–Biedl syndrome: results of a population survey. J Med Genet1999; 36: 437–446[Abstract/Free Full Text]
  6. Green JS, Parfrey PS, Harnet JD et al. The cardinal manifestations of Bardet–Biedl syndrome, a form of Laurence– Moon–Biedl syndrome. N Engl J Med1989; 321: 1002–1009[Abstract]
  7. Elbedour K, Zucker N, Zalzstein E, Barki Y, Carmi R. Cardiac abnormalities in the Bardet–Biedl syndrome: echocardiographic studies of 22 patients. Am J Med Genet1994; 52: 164–169[ISI][Medline]
  8. O'Dea D, Parfrey PS, Harnett JD, Hefferton D, Cramer BC, Green L. The importance of renal impairment in the natural history of Bardet–Biedl syndrome. Am J Kidney Dis1996; 27: 776–783[ISI][Medline]
  9. Katsanis N, Beales PL, Woods MO et al. (2000) Mutations in MKKS cause obesity, retinal dystrophy and renal malformations associated with Bardet–Biedl syndrome. Nature Genet1989; 26: 67–70
  10. Burghes AHM, Vaessin HEF, de la Chapelle A. The land between Mendelian and multifactorial inheritance. Science2001; 293: 2213–2214[Free Full Text]
  11. Sheffield VC, Nishimura D, Stone EM. The molecular genetics of Bardet–Biedl syndrome. Curr Opin Genet Dev2001; 11: 317–321[ISI][Medline]




This Article
Extract
FREE Full Text (PDF)
Alert me when this article is cited
Alert me if a correction is posted
Services
Email this article to a friend
Similar articles in this journal
Similar articles in ISI Web of Science
Similar articles in PubMed
Alert me to new issues of the journal
Add to My Personal Archive
Download to citation manager
Disclaimer
Request Permissions
Google Scholar
Articles by Magen, D.
Articles by Zelikovic, I.
PubMed
PubMed Citation
Articles by Magen, D.
Articles by Zelikovic, I.