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Background: GATA3 encodes a transcription factor critical for embryonic development of the parathyroid glands, kidney, inner ear, thymus, and the central nervous system. Heterozygous loss-of-function mutations in GATA3 are associated with hypoparathyroidism, sensorineural deafness and renal disease (HDR syndrome). Clinical Case: A 12 yo male with left hip pain underwent a closed reduction for left slipped capital femoral epiphysis. The pre-op evaluation revealed hypocalcemia (serum Ca 7.7 mg/dL; nl: 8.8-10.2), creatinine 0.46 mg/dL (0.5-1.0), TSH 3.16 uU/mL (0.3-4.2), FT4 1.36 ng/dL (0.8-1.8). Oral calcium and vitamin D supplementation was begun, and 2 wks later, follow-up evaluation revealed serum Ca of 9.4 mg/dL, intact PTH 4.6 pg/mL (10-69), phosphorus 5.9 mg/dL (3.3-5.3), 25-OHD 26 ng/mL (30-100), and a normal chromosomal microarray. Bone density (DXA) Z-scores for hip and spine were -1.7 and 0.8, respectively. At age 13 he underwent bilateral osteotomy due to bilateral hip dysplasia and removal of hardware the next year. At age 15 he underwent left total hip replacement for avascular necrosis. In the post-operative period hypocalcemia recurred (5.9-6.7mg/dL), and he was referred for endocrine evaluation. He was of mixed African American and Puerto-Rican descent. He had difficulties in school and required eyeglasses and hearing aids. Past history included congenital scoliosis (right T11-12 rib fusion, wedged L1 vertebra, and incomplete fusion of posterior elements of L4 and L5), a small right kidney (per ultrasound examination), bilateral orchiopexy for undescended testicles (age 2), diagnoses of ADHD (at age 5); sensorineural hearing loss and psoriasis (age 12), and gastroesophageal reflux (age13). Multiple paternal family members were reported to have abnormal calcium levels and hearing/vision problems, but no known diagnosis. On exam, he had no facial dysmorphism, but left supernumerary nipples, lumbar lordosis and thoracic kyphosis, and clinodactyly. He had achieved Tanner 5 secondary sexual characteristics. There was no Chvostek’s sign. Laboratory investigation revealed Ca 7.9 mg/dL, phosphorus 5.9 mg/dL (3.1-4.7), alkaline phosphatase 123 U/L (50-380), 25-OHD 32 ng/mL, intact PTH 10.2 pg/mL. Treatment with calcium carbonate and calcitriol was begun. Whole exome sequencing identified a heterozygous mutation in GATA3 (c.1061C>T, p.Pro354Leu), predicted to be damaging. This variant has not been reported in literature or public database to our knowledge. Conclusion: This case highlights the importance of genetic testing in the setting of unexplained hypoparathyroidism, and identifies a likely novel mutation in GATA3, providing a basis to counsel the family and encourage medical follow up of suspected family members. References: Barakat, A., et al., Familial nephrosis, nerve deafness, and hypoparathyroidism. J Pediatr 91:61-64, 1977

Background: AMP-activated protein kinase (AMPK) is implicated in several aspects of lipid metabolism including the suppression of de novo lipogenesis, promotion of fatty acid oxidation, and regulation of adipose tissue biology. We report a patient with severe hypertriglyceridemia harboring a heterozygous mutation in the PRKAA1 gene which codes for the α1-subunit of AMPK. Clinical case: A 22-year-old Mexican woman with history of morbid obesity and T2DM presented with eruptive xanthomas in the upper and lower extremities, back, and chest. VS:141/80, P 86, RR 20, 122 kg BMI 43.42 kg/m2. She was misdiagnosed on multiple occasions and had been treated with steroids until a biopsy revealed foamy histiocytes consistent with xanthomas. A lipid panel showed Triglycerides 8,513 mg/dl (0-150 mg/dl) Cholesterol 555 mg/dl (0-199 mg/dl) HDL 29 mg/dl (≥ 41 mg/dl) Direct LDL 44 (0-99). There was no family history of hyperlipidemia. After ~24-months of follow-up abnormal lipid levels persisted: Triglycerides 4527-8513 mg/dl (0-150 mg/dl) Cholesterol 408-555 mg/dl (0-199 mg/dl) HDL 22-29 mg/dl (≥ 41 mg/dl). She had microalbuminuria 87.7 mcg/mg (0-29.9 mcg/mg) and an HbA1c of 7.8%. She endorsed depression and was inconsistent with her diet due to insatiable appetite but reported medication compliance. Lipoprotein electrophoresis showed a pattern consistent with type IV Hyperlipoproteinemia. Sequencing of lipid metabolism genes revealed no abnormalities but upon whole exome scanning she was found to have a heterozygous nonsense variant in PRKAA1 (exon4:c.C394T:p.Q132X) which codes for the α1-subunit of AMPK resulting in a premature stop codon. We hypothesize that this variant results in defective AMPK activity, and given the role of AMPK in lipid and adipose tissue metabolism, it may result in disinhibition of lipogenesis, reduced fatty acid oxidation, and altered adipose tissue biology, together promoting extreme hypertriglyceridemia. Conclusion: This is the first case to implicate a PRKAA1 gene mutation as a cause of severe hypertriglyceridemia in humans.

Two different mutations in the c-erbA beta thyroid hormone receptor have recently been reported as genetic abnormalities responsible for the syndrome of generalized thyroid hormone resistance (GTHR). We have now found in a third kindred, D, in which GTHR is inherited as a dominant disease, a new point mutation in the T3-binding domain of c-erbA beta. A guanine to cytosine base substitution at nucleotide position 1305, which altered codon-335 from glutamine (CAG) to histidine (CAC), was found in one allele of 10 affected members and was not found in 6 unaffected members. This C-1305 sequence was not present in 106 random alleles, indicating that it was a mutation in c-erbA beta, and it was tightly linked to GTHR in kindred D, with a maximum logarithm of the odds score of 4.19 at a recombination fraction of 0. The tight linkage result confirms that GTHR maps to the c-erbA beta locus in multiple kindreds. In view of the tight linkage between the C-1305 mutation and GTHR, and that this mutation is a nonconservative alteration in a crucial region of the T3-binding domain, it is probably the genetic defect in kindred D responsible for GTHR. The kindred D receptor appears to result in a different phenotype of tissue resistance compared to the previously reported kindred. A receptor with a mutation in the carboxy-terminus of c-erbA beta.

We examined the GnRH gene structure in a family with familial central precocious puberty (eight members, four affected) and a family with idiopathic hypogonadotropic hypogonadism (eight members, three affected) using Southern blot analysis and sequencing of cloned polymerase chain reaction products. Genomic DNA samples were digested with restriction enzymes and hybridized to the human placental GnRH cDNA probe. BamHI digests revealed 6.5- and 2.7-kilobase (kb) bands; BglII, 6.0- and 4.0-kb bands; Ncol, 8.0- and 3.5-kb bands; Pstl, 4.2-kb, 2.8-kb, 1.3-kb and 950-basepair bands; XbaI, 6.5- and 5.0-kb bands. These sizes were the same as those found by this analysis in normal individuals. All family members with familial central precocious puberty or idiopathic hypogonadotropic hypogonadism showed the same size bands, except for one unaffected member of the family with idiopathic hypogonadotropic hypogonadism who had an additional band at 5.5 kb after digestion with NcoI, which is thought to be a rare polymorphism. Sequencing of exon 2 of the GnRH gene from these families, including the exon-intron borders, revealed a polymorphism in the signal sequence of GnRH that predicts an amino acid change from tryptophan (nucleotide sequence: TGG) to serine (TCG) at the -8 position of the GnRH preprohormone. Although this polymorphism did not cosegregate with the clinical disorder in either family, this novel polymorphism may prove useful in the evaluation of linkage to the GnRH gene in other families with pubertal disorders. No other nucleotide sequence abnormality was found in 1.2 kb of the 5' flanking region or the four exons and their splice sites.