Functional characterization of GATA3 mutations causing the hypoparathyroidism-deafness-renal (HDR) dysplasia syndrome: insight into mechanisms of DNA binding by the GATA3 transcription factor.

The hypoparathyroidism-deafness-renal (HDR) dysplasia syndrome is an autosomal dominant disorder caused by mutations of the dual zinc finger transcription factor, GATA3. We investigated 21 HDR probands and 14 patients with isolated hypoparathyroidism for GATA3 abnormalities. Thirteen different heterozygous germline mutations were identified in patients with HDR. These consisted of three nonsense mutations, six frameshifting deletions, two frameshifting insertions, one missense (Leu348Arg) mutation and one acceptor splice site mutation. The splice site mutation was demonstrated to cause a pre-mRNA processing abnormality leading to the use of an alternative acceptor site 8 bp downstream of the normal site, resulting in a frameshift and prematurely terminated protein. Electrophoretic mobility shift assays (EMSAs) revealed three classes of GATA3 mutations: those that lead to a loss of DNA binding which represent over 90% of all mutations, and involved a loss of the carboxy-terminal zinc finger; those that resulted in a reduced DNA-binding affinity; and those (e.g. Leu348Arg) that did not alter DNA binding or the affinity but likely altered the conformational change that occurs during binding in the DNA major groove as predicted by a three-dimensional modeling. These results elucidate further the molecular mechanisms underlying the altered functions of mutants of this zinc finger transcription factor and their role in causing this developmental anomaly. No mutations were identified in patients with isolated hypoparathyroidism, thereby indicating that GATA3 abnormalities are more likely to result in two or more of the phenotypic features of the HDR syndrome and not in one, such as isolated hypoparathyroidism.

Central and gonadal hypogonadism in X-linked lissencephaly.

OBJECTIVE: To directly test gonadal function in a patient with X-linked lissencephaly with ambiguous genitalia (XLAG) in light of lack of previous functional data. STUDY DESIGN AND RESULTS: We studied an infant who failed to increase testosterone levels in response to hCG stimulation. CONCLUSION: In XLAG, the gonads are not only structurally dysgenetic but also functionally abnormal.

Thyroid nodules and cancers in children.

Thyroid nodules are clinically evident in approximately 1% of children and about 30% of these are malignant. In addition to requiring appropriate surgery, thyroid hormone replacement in and follow-up monitoring of patients who are members of families with tumor syndromes must be studied for other components of these syndromes.

Endocrine manifestations of craniopharyngioma.

RATIONALE: Due to the proximity of craniopharyngiomas to the hypothalamus and pituitary gland, most children and adolescents presenting with these tumors will exhibit significant endocrine dysfunction. After treatment, these impairments can become a major cause of morbidity and mortality. METHODS: The postoperative course of children undergoing surgery for craniopharyngioma is reviewed. CONCLUSION: Even if hormone levels seem to be adequate in the short term after treatment, deficiencies may develop over years and need to be monitored closely.

Evaluating short stature in children.

A child's growth reflects his or her general state of health. Growth deceleration therefore may result from processes that ultimately threaten much more than height and weight. Accurate height and weight measurements and routine plotting of growth data on standard growth charts are important elements of pediatric practice. A decrease in length of height percentiles may be physiologic in infancy and in puberty. However, in order to distinguish physiologic from pathologic growth deceleration, a careful history and physical examination needs to be obtained. Quite frequently, laboratory and radiographic studies are needed to distinguish with confidence between causes of slow growth in these phases of life. Such studies are always required to evaluate growth deceleration during childhood, because growth deceleration in this phase is virtually always the result of a pathological process. If constitutional growth delay is diagnosed, reassurance is often adequate treatment, though continued monitoring of growth and bone age is indicated. Growth deceleration due to other processes is often treatable. Delineation of the causes of poor growth is particularly important because these disease processes may produce other serious problems.

Managing growth hormone treatment in pediatric patients.

In general, GH is a safe medication. Patients overwhelmingly enjoy its benefits. Infrequently, its side effects produce worrisome problems. Knowledge of these effects may allow families to choose treatment more judiciously and may allow physicians to detect adverse effects at an early stage.

Coordinating care for children with Turner syndrome.

Turner syndrome is a systemic disease requiring a multi-system management approach. This includes attention to the endocrine system, cardiovascular system, renal system, gastrointestinal system, ears, eyes, skeletal system, and skin, as well as to the psychology of the patient and the family. The primary care physician is central to the care of these patients. In addition to anticipating, diagnosing, and treating the various problems that may arise in patients with Turner syndrome, the primary care physician must coordinate the fairly large healthcare team needed for optimal care.