Fenella Greig

Characterization of novel cathepsin K mutations in the pro and mature polypeptide regions causing pycnodysostosis.

Cathepsin K, a lysosomal cysteine protease critical for bone remodeling by osteoclasts, was recently identified as the deficient enzyme causing pycnodysostosis, an autosomal recessive osteosclerotic skeletal dysplasia. To investigate the nature of molecular lesions causing this disease, mutations in the cathepsin K gene from eight families were determined, identifying seven novel mutations (K52X, G79E, Q190X, Y212C, A277E, A277V, and R312G). Expression of the first pro region missense mutation in a cysteine protease, G79E, in Pichia pastoris resulted in an unstable precursor protein, consistent with misfolding of the proenzyme. Expression of five mature region missense defects revealed that G146R, A277E, A277V, and R312G precursors were unstable, and no mature proteins or protease activity were detected. The Y212C precursor was activated to its mature form in a manner similar to that of the wild-type cathepsin K. The mature Y212C enzyme retained its dipeptide substrate specificity and gelatinolytic activity, but it had markedly decreased activity toward type I collagen and a cathepsin K-specific tripeptide substrate, indicating that it was unable to bind collagen triple helix. These studies demonstrated the molecular heterogeneity of mutations causing pycnodysostosis, indicated that pro region conformation directs proper folding of the proenzyme, and suggested that the cathepsin K active site contains a critical collagen-binding domain.

Transient congenital hypoparathyroidism: Resolution and recurrence in chromosome 22q11 deletion

Transient congenital hypoparathyroidism (TCHP), with spontaneous resolution in infancy and subsequent recurrence in childhood, has not been associated with a specific cause. We report three patients with TCHP, initially with severe but transient neonatal hypocalcemia. During childhood, recurrence of hypoparathyroidism and recognition of phenotypic features suggested a diagnosis of velocardiofacial syndrome (VCFS). Features specific for the DiGeorge syndrome, with known clinical and genetic overlap with VCFS, were not present except for hypoparathyroidism. Genetic analysis confirmed chromosome 22q11 deletion in each patient. TCHP may be the earliest specific finding in 22q11 deletion/VCFS subgroup, with other diagnostic features emerging in later childhood. Infants with resolved TCHP need continued observation of parathyroid sufficiency, genetic analysis, and examination for anomalies associated with chromosome 22q11 deletion.

Late rise of thyroid stimulating hormone in ill newborns.

OBJECTIVES To determine the frequency and characteristics of late rise of thyroid stimulating hormone (LRT) among ill newborns. INFANTS AND METHODS Data were retrospectively analyzed from infants in intensive care settings with abnormal thyroid tests over 13 months. Thyroid tests were performed by filter paper if neonatal intensive care >4 weeks or serum if clinically indicated. LRT was defined as thyroid stimulating hormone (TSH) >10 microIU/ml after normal TSH on initial newborn screen. RESULTS LRT was identified in 13 infants. Of 736 admissions to the neonatal intensive care unit (NICU), 10 (1.4%) had LRT. Excluding 3/10 with diagnosis at <1 week of age the frequency is 0.95%. Three additional cases occurred in other ICUs. TSH elevation resolved in 6/13 (group A, TSH 10.6-20.6 microIU/ml) and persisted in 7/13 necessitating treatment (group B, TSH 10.5-1326 microIU/ml). 7/13 had birth weights <1500 g. 11/13 had gestational ages <37 weeks. LRT was associated with surgery, sepsis workup, dopamine, and gastrointestinal disorders. CONCLUSIONS LRT was not infrequent in ill newborns. Most were premature and half were not very low birth weight. We recommend monitoring of thyroid function by serum specimen in ill newborns with prolonged ICU care regardless of birth weight.

Characteristics of diabetes after pediatric liver transplant

Greig F, Rapaport R, Klein G, Akler G, Annunziato R, Miloh T, Arnon R, Florman S, Kerkar N. Characteristics of diabetes after pediatric liver transplant.

Which obese youth are at increased risk for type 2 diabetes? Latent class analysis and comparison with diabetic youth

Greig F, Hyman S, Wallach E, Hildebrandt T, Rapaport R. Which obese youth are at increased risk for type 2 diabetes? Latent class analysis and comparison with diabetic youth.

Neonatal Hyponatremic Dehydration as an Initial Presentation of Cystic Fibrosis

concentration of 134 mmol/L, potassium of 3.6 mmol/L, chloride of 95 mmol/L, and bicarbonate of 26 mmol/L. On day 3, fluid intake totaled 109 mL/kg with 2.7 mmol/kg of sodium. On day 4 the baby, now on full oral intake, received 116 mL/kg of fluid, 1.7 mmol/kg of sodium, and 2.9 mmol/kg of potassium. At 96 hours of age, the baby appeared clinically dehydrated. His weight, which had decreased slowly from birth, dropped further, with a total loss of 12.8%. Vital signs included blood pressure of 54/30 mm Hg, pulse of 190/min, and rectal temperature of 98.4°F. He had urinated only once in the preceding 24 hours. There was no fluid loss from vomiting or nasogastric drainage. Meconium had been replaced by normal stools after three days. Serum electrolyte concentrations included sodium

Newborn Thyroid Screening:Hidden Burden of Screening by Primary Thyroxine Test |[dagger]| 430

Newborn screening to identify congenital hypothyroidism (CH) may employ primary thyrotropin (TSH), or primary thyroxine (T4) measurement with added TSH for the lowest 10% of T4 cases. Primary T4 screening, used in most USA programs, balances a risk of missing cases of compensated hypothyroidism with the benefit of identifying tertiary hypothyroidism, but includes other causes of low T4 which do not require treatment (Rx). A recent report (NEJM 1997;336:21-6) suggested there should be less concern for untreated low T4 in premature infants. In addition, an increase in concern for spiraling medical costs prompted our re-examination of the heterogeneous group identified by low T4 screening. We also examined the follow-up work necessary to achieve resolution (demonstrate normality or treat hypothyroidism). An 8 year retrospective survey of infants referred to one center for endocrine evaluation of abnormal thyroid screening tests included 112 cases from 43,054 births plus 793 transports to this hospital.

Improved Glycemic Control After 12 Months Use of Humalog Insulin † 479

Humalog insulin has been available for use since August 1996. In prior studies performed in children, the addition of Humalog led to lower postprandial blood sugars, fewer nocturnal hypoglycemic events, and increased convenience with respect to meal timing. However, HgbA1C values were not significantly lower. We have a large pediatric population of patients with type 1 diabetes using Humalog. We did a chart review of our patients using Humalog for all or part of their rapid acting insulin for at least 6 months. To be included, patients had to have been diagnosed at least 1.5 years prior to beginning Humalog and must have been on a regimen in the past that did not contain Humalog. 49 charts were chosen randomly for review after meeting the above criteria. A1C values at 3, 6 and 12 months after starting Humalog were compared to the average A1C during the six months prior to starting Humalog. Table 1 shows average A1C values. Normal A1C < 6.4.