Syndromic obesity: clinical implications of a correct diagnosis
- Donatella Milani†1,
- Marta Cerutti†1,
- Lidia Pezzani1,
- Pietro Maffei2,
- Gabriella Milan2 and
- Susanna Esposito1Email author
© Milani et al.; licensee BioMed Central Ltd. 2014
Received: 12 February 2014
Accepted: 28 March 2014
Published: 2 April 2014
Although individual occurrence is rare, syndromic obesity with mental retardation has been reported in conjunction with 140 different diseases.
The patient was born at term after a pregnancy complicated by threatened miscarriage. A diagnosis of Bardet-Biedl syndrome (BBS; OMIM #209900) was made in another hospital when she was 8 years old, but other clinical problems emerged subsequently. She came to our attention for the first time when she was 14 years old. The clinical picture, characterized by the presence of ophtalmological, renal, endocrinological, and liver disorders associated with a peculiar weight growth pattern, was more suggestive for Alström syndrome (ALMS; OMIM #203800); consequently, a genetic study was performed. Genetic analysis revealed a novel compound heterozygous frameshift mutation on exon 8 of ALMS1 (c. [3251_3258delCTGACCAG] and c. [6731delA]), which has not previously been described.
Early onset of retinal degeneration associated with obesity represents a diagnostic challenge in paediatric and genetic practice, although the absence of skeletal abnormalities and developmental delay could help in addressing the clinical diagnosis. Confirmation of clinical suspicion by genetic analysis has been diriment in this case, since only a single gene is known to cause ALMS.
KeywordsAlström syndrome Bardet-Biedl syndrome Cone-rod dystrophy Obesity Syndromic obesity
Diagnosis is made when the following criteria are present:
Diagnosis is made when:
2 major OR 1 major + 2 minor
4 major criteria are present OR
2 major OR 1 major + 3 minor
3 major plus 2 minor criteria are present
2 major + 2 minor criteria OR 1 major + 4 minor criteria
ALMS 1 mutation in 1 allele and/or family history of ALMS
Vision (nystagmus, photophobia)
ALMS 1 mutation in 1 allele and/or family history of ALMS
Obesity and/or insulin resistance
Polyuria/polidipsia (nephrogenic diabetes insipidus)
Vision (nystagmus, photophobia, decreased acuity, cone dystrophy by ERG)
(History of) DCM/CHF
Hypogonadism in males
Advanced bone age
Mild spasticity (especially lower limbs)
ALMS 1 mutation in 1 allele and/or family history of ALMS
Obesity and/or insulin resistance and/or DM2
Dental crowding/hypodontia/small roots/high arched palate
Vision (legal blindness, history of nystagmus in infancy/childhood, cone and rode dystrophy by ERG)
(History of) DCM/CHF
Left ventricular hypertrophy/congenital heart disease
Females-irregular menses and/or hyperandrogenism
To date, 18 genes (BBS1-18) are known to be associated with BBS, whereas only one gene has been identified for ALMS[5, 9]. Nevertheless, overlapping phenotypes have been reported between ALMS and BBS[10–12].
In syndromes with overlapping clinical signs but different natural history, major complications and follow-up, differential diagnosis can be challenging in order to assess a specific management and treatment regimen. In this paper, we report a patient previously diagnosed with BBS who was reassessed for a clinical and genetic diagnosis of ALMS.
Our patient is the only daughter of unrelated healthy parents, and family history was unremarkable for genetic diseases. She was born at term after a pregnancy complicated by threatened miscarriage. Her birth weight was 3,480 g, with a birth length of 48.5 cm, occipital frontal circumference of 33.5 cm, and APGAR score 9/10. Since the first months of life, nystagmus and exotropia were noticed, and a retinopathy with severe low vision (1/20) was subsequently diagnosed. Retinal hypopigmentation and peripheral atrophy with extension to macular region were detected in the first years of life, and lack of response was demonstrated with electroretinogram and visual evoked potentials. Leber’s congenital amaurosis was initially suspected. In addition, the pattern of growth was always over 2 standard deviations for weight centile. In accordance with the presence of these features, a diagnosis of BBS was made in another hospital when she was 8 years old. However, other clinical problems emerged subsequently. The ocular anterior segment was initially normal, but a left cortical cataract emerged when the patient was 12 years old. Moreover, biochemical investigation showed hypertriglyceridemia, high LDL-cholesterol, low HDL-cholesterol, and increased insulin and C-peptide levels with a normal value of hemoglobin A1c. Hepatic dysfunction with hypertransaminasemia and mild cholestasis was further investigated by ultrasound evaluation that showed liver steatosis. Mild hypertension and thickening of cardiac mass were detected shortly after by cardiologic examination, and mild micro-albuminuria and proteinuria were discovered by urine analysis. The patient was also treated for precocious puberty; after the stop of therapy, hirsutism, hyperadrogenism, and later oligoamenorrhoea were detected. She also suffered from scoliosis and restrictive pulmonary dysfunction. Additionally, bilateral sensorineural hearing loss for high frequencies was detected since she was 13 years old. No mental retardation or any signs of motor or speech delay were ever reported. A neurological evaluation was only requested for muscle cramps during adolescence; on that occasion, a suspicion of a mitochondrial disease was formulated due to the clinical spectrum of signs, but no imbalance of mitochondrial chain was confirmed.
The range of biological causes that account for childhood obesity is heterogeneous, with several reports of multi-systemic monogenic disorders. Many of these disorders have a peculiar presentation but could have an overlapping phenotype, indicating the likelihood of a shared common underlying pathway. This is well represented by BBS and ALMS, both classified as “ciliopathies” according to the aetiology. Clinical overlap between these two entities has been described, although BBS and ALMS are genetically distinct. In our patient there was no evidence of poly or syndactyly suggestive for BBS, and retinal dystrophy was observed since the first months of life. This stands in contrast with BBS, where retinal dystrophy is a nearly constant finding at over 5 years of age[6, 10, 15]. Moreover, complete blindness usually occurs in the second decade of life in ALMS, and bilateral subcapsular cataracts are also common. In our patient, sensorineural hearing loss for high frequencies, a peculiar feature described in 89% of individuals with ALMS, was also detected. The diagnosis of BBS was questioned by the presence of early onset retinal degeneration, insulin resistance, the absence of polydactyly, and relative preservation of cognitive function. Although ALMS may be difficult to diagnose because of its rarity and age dependent phenotype, early detection of the syndrome would allow clinicians to recognize the progressive development of a multi-organ pathology that can lead to reduced life expectancy, allowing for the establishment of a specific follow-up procedure and supportive therapy. In particular, the development of a heart failure, diabetes mellitus, obesity, liver and renal dysfunction could negatively interact, and they must be suspected and/or treated early.
Early onset retinal degeneration associated with obesity represents a diagnostic challenge in paediatric and genetic practice, although the absence of skeletal abnormalities and developmental delay could facilitate clinical diagnosis. Careful medical history and clinical examination remain the cornerstones of diagnosis. Confirmation of clinical suspicion by genetic analysis has been diriment in this case since ALMS has been associated with a single causative gene, implying a faster diagnostic process with a lower economic impact. Within the last few years, research into the pathogenesis of ALMS has led to better management and treatment not only for this condition, but also for more common ciliopathies. Ultimately, the monogenic model of ALMS may facilitate the understanding of the biochemical pathways of more common diseases affecting the general population, such as obesity, diabetes, or single organ failure diseases.
Written informed consent was obtained from the parents for publication of this Case report. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Body mass index
Dilated cardiomyopathy with congestive heart failure
Type 2 diabetes mellitus
Polymerase chain reaction.
The authors thank the patient for her kind availability for this study.
- D’Angelo CS, Kohl I, Varela MC, de Castro CI, Kim CA, Bertola DR, Lourenço CM, Perez AB, Koiffmann CP: Obesity with associated developmental delay and/or learning disability in patients exhibiting additional features: report of novel pathogenic copy number variants. Am J Med Genet A. 2013, 161 (Suppl 3): 479-486.View ArticleGoogle Scholar
- Beales PL, Elcioglu N, Woolf AS, Parker D, Flinter FA: Criteria for improved diagnosis of Bardet-Biedl syndrome: results of a population survey. J Med Genet A. 1999, 36 (Suppl 6): 437-446.Google Scholar
- Alstrom CH, Halgren B, Nilsson LB, Asander H: Retinal degeneration combined with obesity, diabetes mellitus and neurogenous deafness: a specific syndrome (not hitherto described) distinct from the Laurence-Moon-Bardet-Biedl syndrome: a clinical, endocrinological and genetic examination based on a large pedigree. Acta Psychiatr Neurol Scand Suppl. 1959, 129: 1-35.PubMedGoogle Scholar
- Marshall JD, Maffei P, Collin GB, Naggert JK: Alström syndrome: genetics and clinical overview. Curr Genomics. 2011, 12: 225-235. 10.2174/138920211795677912.PubMed CentralView ArticlePubMedGoogle Scholar
- Aliferis K, Hellé S, Gyapay G, Duchatelet S, Stoetzel C, Mandal JL, Dollfus H: Differentiating Alström from Bardet-Biedl syndrome (BBS) using systematic ciliopathy genes sequencing. Ophthalmic Genet. 2012, 33 (Suppl 1): 18-22.View ArticlePubMedGoogle Scholar
- Putoux A, Attie-Bitach T, Martinovic J, Gubler MC: Phenotypic variability of Bardet-Biedl syndrome: focusing on the kidney. Pediatr Nephrol. 2012, 27: 7-15. 10.1007/s00467-010-1751-3.View ArticlePubMedGoogle Scholar
- Zaghloul NA, Katsanis N: Mechanistic insights into Bardet-Biedl syndrome, a model ciliopathy. J Clin Invest. 2009, 119: 428-437. 10.1172/JCI37041.PubMed CentralView ArticlePubMedGoogle Scholar
- EURO_WABB project.http://www.euro-wabb.org/it/lovd-genetic-variation-database-it,
- Collin GB, Marshall JD, Ikeda A, So WV, Russell-Eggitt I, Maffei P, Beck S, Boerkoel CF, Sicolo N, Martin M, Nishina PM, Naggert JK: Mutations in ALMS1 cause obesity, type 2 diabetes and neurosensory degeneration in Alström syndrome. Nat Genet. 2002, 31: 74-78.PubMedGoogle Scholar
- Billingsley G, Bin J, Fieggen KJ, Duncan JL, Gerth C, Ogata K, Wodak SS, Traboulsi EI, Fishman GA, Paterson A, Chitayat D, Knueppel T, Millán JM, Mitchell GA, Deveault C, Héon E: Mutations in chaperonin-like BBS genes are a major contributor to disease development in a multiethnic Bardet-Biedl syndrome patient population. J Med Genet A. 2010, 47 (Suppl 7): 453-463.Google Scholar
- Pereiro I, Hoskins BE, Marshall JD, Collin GB, Naggert JK, Piñeiro-Gallego T, Oitmaa E, Katsanis N, Valverde D, Beales PL: Arrayed primer extension technology simplifies mutation detection in Bardet-Biedl and Alström syndrome. Eur J Hum Genet. 2011, 19 (Suppl 4): 485-488.PubMed CentralView ArticlePubMedGoogle Scholar
- Redin C, Le Gras S, Mhamdi O, Geoffroy V, Stoetzel C, Vincent MC, Chiurazzi P, Lacombe D, Ouertani I, Petit F, Till M, Verloes A, Jost B, Chaabouni HB, Dollfus H, Mandel JL, Muller J: Targeted high-throughput sequencing for diagnosis of genetically heterogeneous diseases: efficient mutation detection in Bardet-Biedl and Alström syndromes. J Med Genet. 2012, 49 (Suppl 8): 502-512.PubMed CentralView ArticlePubMedGoogle Scholar
- den Dunnen JT, Antonarakis E: Nomenclature for the description of human sequence variations. Hum Genet. 2001, 109: 121-124. 10.1007/s004390100505.View ArticlePubMedGoogle Scholar
- Goldstone AP, Beales PL: Genetic obesity syndromes. Front Horm Res. 2008, 36: 37-60.View ArticlePubMedGoogle Scholar
- Mockel A, Perdomo Y, Stutzmann F, Letsch J, Marion V, Dollfus H: Retinal dystrophy in Bardet-Biedl syndrome and related syndromic ciliopathies. Prog Retin Eye Res. 2011, 30 (Suppl 4): 258-274.View ArticlePubMedGoogle Scholar
- Russell-Eggitt IM, Clayton PT, Coffey R, Kriss A, Taylor DSI, Taylor JFN: Alström syndrome. Report of 22 cases and literature review. Ophthalmol. 1998, 105: 1274-1280. 10.1016/S0161-6420(98)97033-6.View ArticleGoogle Scholar
- Marshall JD, Beck S, Maffei P, Naggert JK: Alström syndrome. Eur J Hum Genet. 2007, 15: 1193-1202. 10.1038/sj.ejhg.5201933.View ArticlePubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.