EARLY ONSET OF MODY5 DUE TO HAPLOINSUFFICIENCY OF HNF1B.

OBJECTIVE: To report 2 patients with haploinsufficiency of hepatic nuclear factor 1 homeobox B (HNF1B) that results in the onset of maturity onset diabetes of the young type 5 (MODY5) before 3 years of age. METHODS: We present 2 unusual patients with MODY5 that was diagnosed at 33 and 22 months of age, respectively. We describe the presentations, clinical course, and genetic tests of both patients, and lastly, we review the literature on the prevalence and the age of presentation of MODY5 both in children and in adult patients. RESULTS: The first patient had severe congenital renal dysplasia, and deoxyribonucleic acid microarray indicated the deletion of 17q12. Hemoglobin A1c (HbA1c) was obtained due to the concern of MODY5, and the initial level (6.6%, 49 mmol/mol) was abnormally elevated. The second patient had mild renal dysplasia and 17q12 deletion encompassing the HNF1B gene. Hyperglycemia was identified during an episode of respiratory illness. HbA1c (6.2%, 44 mmol/mol) level was abnormally elevated. Pancreatic autoantibodies were absent in both patients. Diet modification resulted in an improvement of HbA1c in both patients. CONCLUSION: Our report highlights the importance of considering MODY5 in patients with congenital anomalies of kidney. Identification of children with MODY5 permits early management of hyperglycemia.

Vitamin D status among preterm infants with cholestasis and metabolic bone disease.

BACKGROUND: Metabolic bone disease of prematurity (MBD) is a common problem among preterm infants. Our previous study identified cholestasis as an important risk factor for the development of MBD. We conducted this study to determine the vitamin D status in preterm infants with MBD and cholestasis. METHODS: We retrospectively reviewed medical record of preterm infants evaluated in NICU at Holtz Children's/Jackson Memorial Hospital between June 2014 and May 2016. Demographic, biochemical data, and vitamin D intake were collected and analyzed. RESULTS: We identified 58 preterm infants (median gestational age 25 weeks) with MBD during this period. Twenty five infants also developed cholestasis. Median serum 25-hydroxyvitamin D level at the time of diagnosis of MBD was similar in cholestasis (C), (29.1 ng/ml, IQR 24.4-33.5), and non-cholestasis (NC), (28.7 ng/ml, IQR 22.7-34.6), group (p = 0.41). At the second measurement, average 6 weeks after the first measurement; median serum 25-hydroxyvitamin D level was lower (p = 0.02) in the C group (31.2 ng/ml, IQR 23.0-38.8) than in the NC group (36.5 ng/ml, IQR 28-45). However, the actual percentage of infants with vitamin D deficiency was similar in both the groups. CONCLUSION: Most preterm infants with cholestasis and MBD had normal vitamin D status.

Risk factors of metabolic bone disease of prematurity.

OBJECTIVE: To identify the factors that increase risk of metabolic bone disease of prematurity (MBD). STUDY DESIGN: A retrospective case-control study of infants born between January 2013-April 2014 with gestation age <30weeks and birth weight <1000g. MBD was defined as serum alkaline phosphatase above 500U/L and characteristic radiographic changes. Information was obtained on the presence of specific comorbidities. RESULTS: Of 76 infants evaluated, 40 met criteria for MBD. Median gestational age was 25weeks in both groups (p=0.512). Median birth weight of infants with MBD was significantly lower than that of controls (560 vs. 765g, p<0.01). Longer period of parenteral nutrition and dexamethasone use was observed in MBD group. Cholestasis was associated with the highest likelihood of MBD (OR 16.6, 95% CI 4.8-56.9). Seizures (OR 5.2, 95% CI 1.3-20.5) and the prolonged use of diuretics (OR 2.6, 95% CI 1.0-7.0) also significantly increased the likelihood of MBD. Only cholestasis remained significant (OR 9.6, 95% CI 2.1-45.3) after multiple regression analysis. CONCLUSION: Cholestasis is a significant risk factor for the development of MBD. Our future studies will be directed towards determining the causal relationship between cholestasis and MBD.

Early recognition of gonadal dysgenesis in congenital nephrotic syndrome
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Mutation of the Wilms tumor suppressor gene (WT1) has been recognized as one of the etiologies of steroid-resistant nephrotic syndrome (SRNS). The mutation is also responsible for gonadal dysgenesis in 46,XY individuals. Early recognition of the presence of Y chromosome is of particular importance because of the high risk of gonadal tumor. We present here three cases of steroid-resistant nephrotic syndrome with WT1 mutation and 46,XY karyotype. Patient 1 and 2 have intron splice site (IVS9+5G A) mutation. Patient 3 has c.1301GA (p. R434H) mutation. All cases had normal female external genitalia at birth and eluded the diagnosis of gonadal dysgenesis until later in life. We suggest that chromosomal analysis should be promptly performed in female patients with early-onset steroid-resistant nephrotic syndrome.
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Childhood hypophosphatasia with homozygous mutation of ALPL.

OBJECTIVE: To describe an unusual phenotype of a case with rare homozygous ALPL gene mutation that results in mild form of hypophosphatasia. METHODS: Case presentation, description of biochemical profiles, genetic testing and a brief review of literature are presented. RESULTS: A 13-year-old male presented with chronic left knee pain. Radiogram of the left knee indicated two oval radiolucent lesions in the femoral metaphysis. Serum alkaline phosphatase activity (17 U/L) was markedly below normal (42 to 362 U/L). Serum pyridoxal 5' phosphate (258 µg/L) was above normal (5 to 50 µg/L). Sequence analysis of ALPL gene indicated a homozygous missense mutation c.1077 C>G (p. I359M). The mutation was previously identified in a case of perinatal hypophosphatasia with severe skeletal abnormalities in contrast to the mild phenotype of the patient we present. CONCLUSION: The case of homozygous mutation of ALPL gene but mild form of hypophosphatasia suggests that functions of the mutated protein may be modified by other factors.

Duplication of SOX9 is not a common cause of 46,XX testicular or 46,XX ovotesticular DSD.

BACKGROUND: Translocation of the SRY gene to the paternal X chromosome is the explanation for testis development in the majority of subjects with 46,XX testicular disorder of sexual development (DSD). However, nearly all subjects with 46,XX ovotesticular DSD and up to one third of subjects with 46,XX testicular DSD lack SRY. SRY-independent expression of SOX9 has been implicated in the etiology of testis development in some individuals. METHODS: We amplified microsatellite markers in the region of SOX9 from a cohort of 30 subjects with either 46,XX testicular or 46,XX ovotesticular DSD to detect SOX9 duplications. RESULTS: Duplication of the SOX9 region in 17q was not detected in any subject. CONCLUSION: Duplication in the region of 17q that contains SOX9 is not a common cause of testis development in subjects with SRY-negative 46,XX testicular or ovotesticular DSD.

Megakaryocyte development is normal in mice with targeted disruption of Tescalcin.

BACKGROUND: Tescalcin is an EF-hand calcium-binding protein that interacts with the Na+/H+ exchanger 1 (NHE1). Levay and Slepak recently proposed a role for tescalcin in megakaryopoiesis that was independent of NHE1 activity. Their studies using K562 and HEL cell lines, and human CD34+ hematopoietic stem cells suggested an essential role for tescalcin in megakaryocyte differentiation. OBJECTIVE: To study the role of tescalcin in megakaryocyte development using a murine model of megakaryopoiesis. METHODS: We generated a mouse with targeted disruption of tescalcin and investigated megakaryocyte development. RESULTS: Tescalcin-deficient mice had a normal number of megakaryocytes and platelets. The morphology, polyploidization profile, and expression of Fli-1 in bone marrow-derived megakaryocytes were also normal. CONCLUSION: Tescalcin does not appear to be necessary for normal megakaryocyte development.