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Syndromic obesity: clinical implications of a correct diagnosis.

Milani D, Cerutti M, Pezzani L, Maffei P, Milan G, Esposito S - Ital J Pediatr (2014)

Bottom Line: She came to our attention for the first time when she was 14 years old.The clinical picture, characterized by the presence of ophthalmological, 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Pediatric Highly Intensive Care Unit, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Via Commenda 9, Milano 20122, Italy. susanna.esposito@unimi.it.

ABSTRACT

Background: Although individual occurrence is rare, syndromic obesity with mental retardation has been reported in conjunction with 140 different diseases.

Case presentation: 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 ophthalmological, 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.

Conclusion: 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.

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Related in: MedlinePlus

Two novel heterozygous frameshift mutations were detected in the proband. Panels show the chromatograms of the forward sequences relative to the regions on exon 8 in which the deletions (indicated by the arrows) are located, at positions 3251 and 6731 from the ATG of the coding sequence (c.) of ALMS1 mRNA (NM_015120.4), respectively. The position of the frameshift (fs) and of the predicted premature termination codon (*) at the protein sequence level is indicated (p.). Nomenclature of mutations is according to den Dunnen JT and Antonarakis E[13].
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Figure 2: Two novel heterozygous frameshift mutations were detected in the proband. Panels show the chromatograms of the forward sequences relative to the regions on exon 8 in which the deletions (indicated by the arrows) are located, at positions 3251 and 6731 from the ATG of the coding sequence (c.) of ALMS1 mRNA (NM_015120.4), respectively. The position of the frameshift (fs) and of the predicted premature termination codon (*) at the protein sequence level is indicated (p.). Nomenclature of mutations is according to den Dunnen JT and Antonarakis E[13].

Mentions: She came to our attention for the first time when she was 14 years old. The clinical picture, characterized by the presence of ophthalmological, renal, endocrinological, and liver disorders associated with a peculiar weight growth pattern (Figure 1) was more suggestive of ALMS, and consequently a genetic study was performed. Genomic DNA, isolated from peripheral blood of the patient according to standard methods, was amplified using a standard polymerase chain reaction (PCR) protocol with HotStarTaq Master Mix Kit (QIAGEN GmbH, Hilden, Germany). Primer sequences and amplification conditions are available on request. PCR amplicons of exons 8, 10 and 16 of ALMS1 were purified, directly sequenced using ABI PRISM Big Dye Terminator Cycle sequencing Ready Reaction Kits, and analyzed with an ABI 3100 Sequencing Analyzer (Applied Biosystems, Forster City, CA, USA). Resulting sequences were compared with the GenBank mRNA reference sequence (NM_015120.4) using ClustalW2 (http://www.ebi.ac.uk/Tools/clustalw2/index.html). The nomenclature of mutations was assigned according to den Dunnen and Antonarakis[13]. Genetic analysis revealed a novel compound heterozygous frameshift mutation on exon 8 of ALMS1 (c. [3251_3258delCTGACCAG] and c. [6731delA]; Figure 2), which has not been described previously. Both mutations result in a premature termination codon and truncation of the protein.


Syndromic obesity: clinical implications of a correct diagnosis.

Milani D, Cerutti M, Pezzani L, Maffei P, Milan G, Esposito S - Ital J Pediatr (2014)

Two novel heterozygous frameshift mutations were detected in the proband. Panels show the chromatograms of the forward sequences relative to the regions on exon 8 in which the deletions (indicated by the arrows) are located, at positions 3251 and 6731 from the ATG of the coding sequence (c.) of ALMS1 mRNA (NM_015120.4), respectively. The position of the frameshift (fs) and of the predicted premature termination codon (*) at the protein sequence level is indicated (p.). Nomenclature of mutations is according to den Dunnen JT and Antonarakis E[13].
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4230022&req=5

Figure 2: Two novel heterozygous frameshift mutations were detected in the proband. Panels show the chromatograms of the forward sequences relative to the regions on exon 8 in which the deletions (indicated by the arrows) are located, at positions 3251 and 6731 from the ATG of the coding sequence (c.) of ALMS1 mRNA (NM_015120.4), respectively. The position of the frameshift (fs) and of the predicted premature termination codon (*) at the protein sequence level is indicated (p.). Nomenclature of mutations is according to den Dunnen JT and Antonarakis E[13].
Mentions: She came to our attention for the first time when she was 14 years old. The clinical picture, characterized by the presence of ophthalmological, renal, endocrinological, and liver disorders associated with a peculiar weight growth pattern (Figure 1) was more suggestive of ALMS, and consequently a genetic study was performed. Genomic DNA, isolated from peripheral blood of the patient according to standard methods, was amplified using a standard polymerase chain reaction (PCR) protocol with HotStarTaq Master Mix Kit (QIAGEN GmbH, Hilden, Germany). Primer sequences and amplification conditions are available on request. PCR amplicons of exons 8, 10 and 16 of ALMS1 were purified, directly sequenced using ABI PRISM Big Dye Terminator Cycle sequencing Ready Reaction Kits, and analyzed with an ABI 3100 Sequencing Analyzer (Applied Biosystems, Forster City, CA, USA). Resulting sequences were compared with the GenBank mRNA reference sequence (NM_015120.4) using ClustalW2 (http://www.ebi.ac.uk/Tools/clustalw2/index.html). The nomenclature of mutations was assigned according to den Dunnen and Antonarakis[13]. Genetic analysis revealed a novel compound heterozygous frameshift mutation on exon 8 of ALMS1 (c. [3251_3258delCTGACCAG] and c. [6731delA]; Figure 2), which has not been described previously. Both mutations result in a premature termination codon and truncation of the protein.

Bottom Line: She came to our attention for the first time when she was 14 years old.The clinical picture, characterized by the presence of ophthalmological, 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Pediatric Highly Intensive Care Unit, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Via Commenda 9, Milano 20122, Italy. susanna.esposito@unimi.it.

ABSTRACT

Background: Although individual occurrence is rare, syndromic obesity with mental retardation has been reported in conjunction with 140 different diseases.

Case presentation: 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 ophthalmological, 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.

Conclusion: 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.

Show MeSH
Related in: MedlinePlus