Pedigree of a CHARGE patient with a novel CHD7 mutation. Unfortunately, neither was available for further characterization.Ī patient with a unique presentation of CHARGE syndrome and a G744S CHD7 mutation. Interestingly, both a full sister and maternal half sister had severe hearing deficits and renal disease (Figure 1A). Our initial consultation for hypocalcemia was during a hospitalization for complications of end stage renal disease secondary to MCDK, which was diagnosed in early life based on X-ray computed tomography (CT) showing dysplastic kidneys with multiple cysts. At a young age, the family had been told that he had Down syndrome, a diagnosis he carried until our meeting. Additionally, he had congenital hypothyroidism, bilateral sensorineural hearing loss, and severe global developmental delay he began walking during his third year of life, remains unable to independently dress or tie shoe laces, and he has a vocabulary of fewer than 5 words. In infancy, he underwent cardiac surgery for a ventricular septal defect, and another to correct a right eyelid coloboma. He was born weighing 795 grams at 25 weeks gestation to a 31-year old woman with severe hypertension, who died in the postpartum period of a myocardial infarction. The proband, an 18 year old African American male, presented to us initially for management of refractory hypocalcemia. Our report expands the spectrum of phenotypes associated with CHD7 mutations. Herein, we report a patient with a unique presentation of CHARGE syndrome, including primary hypoparathyroidism, bilateral multicystic dysplastic kidneys (MCDK), and an atypical limb anomaly he carried a CHD7 mutation that has not been previously characterized. As the CHARGE phenotype continues to expand, particularly into the clinical purview of other conditions, its diagnosis becomes more challenging as well as increasingly inclusive. As such, CHARGE Syndrome has several overlapping clinical characteristics with DiGeorge syndrome, Kallmann syndrome, and Hypoparathyroidism, Sensorineural Deafness, and Renal Disease (HDR) (Barakat's syndrome). A wider spectrum of associated features has since emerged, albeit less consistently, and includes hyposmia or anosmia, cleft lip and palate, hypocalcemia, and tracheoesophageal fistula. It was only in 2004 that the CHD7 gene was established as a genetic etiology for CHARGE syndrome by Vissers et al. The first descriptions of this syndrome were provided by Hall and Hitner independently in 1979, though it was in 1981 that Pagan and colleagues coined the acronym CHARGE to summarize its dominant features: coloboma, heart defects, atresia choanae, retarded growth and development, genital and/or urinary abnormalities, ear anomalies and/or deafness. Furthermore, CHD7 mutations are reported throughout the entire coding sequence of the gene without an apparent pattern or cluster, and meaningful genotype-phenotype correlations have not been recognized. Heterozygous CHD7 (chromodomain helicase DNA-binding protein 7, MIM 608892) mutations have been identified in approximately 60%-70% of patients with clinically diagnosed CHARGE Syndrome and are most commonly due to de novo truncating mutations. The CHARGE syndrome (MIM 214800) is an autosomal dominant or sporadic disorder of variable multisystemic congenital anomalies that occurs with an incidence of approximately 1 in 10,000. Our report continues to expand the CHARGE phenotype and highlights that stringent fulfillment of conventional criteria should not strictly guide genetic analysis. Furthermore, with structural modeling and murine expression studies, we characterize a putative CHD7 G744S missense mutation. We present a patient with a unique manifestation of CHARGE syndrome, including primary hypoparathyroidism and a limb anomaly to our knowledge, he is also the first CHARGE subject reported with bilateral multicystic dysplastic kidneys. With greater accessibility to genetic analysis, a wider spectrum of features are emerging, and overlap with disorders such as DiGeorge syndrome, Kallmann syndrome, and Hypoparathyroidism Sensorineural Deafness and Renal Disease syndrome, is increasingly evident. Classic features include: Coloboma, Heart defects, Atresia choanae, Retarded growth and development, Genitourinary abnormalities, and Ear anomalies and/or deafness. CHARGE is a phenotypically heterogeneous autosomal dominant disorder recognized as a cohesive syndrome since the identification of CHD7 as a genetic etiology.
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