Low-level hyperinsulinism with hypoglycemic spells in an infant with mosaic Turner syndrome and mild Kabuki-like phenotype: a case report and review of the literature.

BACKGROUND: Impaired glucose tolerance and type 2 diabetes are well-known features in patients with Turner syndrome. To the best of our knowledge, there is only one reported case of hyperinsulinemic hypoglycemia associated with a complex mosaic Turner syndrome available in the current literature. PATIENT: We report on the case of a 13-month-old girl with a complex mosaic Turner genotype and mild hyperinsulinemic hypoglycemia responsive to diazoxide therapy. RESULTS: Cytogenetic analyses showed two or possibly three cell lines. Sixty percent of the cell lines had a 45,X genotype and the rest had 46,XX with a marker ring chromosome. Diagnosis of a mosaic Turner syndrome and mild Kabuki-like phenotype was confirmed. CONCLUSIONS: Despite the rareness of this case, clinicians should be aware of the possibility of hyperinsulinemic hypoglycemia in patients with Turner syndrome to prevent further brain damage caused by hypoglycemic episodes and seizures. Although the mechanism leading to hyperinsulinism in this condition is still unknown, the present report discusses this rare presentation and gives an overview on the current literature regarding this case.

Transition of young adults with phenylketonuria from pediatric to adult care.

BACKGROUND: Transition from pediatric to adult health care is a particularly vulnerable period for patients with inborn metabolic diseases. Aim of the present study was to evaluate the current transition situation of patients with phenylketonuria (PKU) in Leipzig, Germany, by analysis of the medical care, metabolic control, patients' satisfaction, socio-economic and psychosocial status, in order to identify areas of weakness and potential improvement. METHODS: Patients who had been transferred from pediatric to adult medical care between 2005 and 2008 were identified. An interview was performed using a questionnaire. Pediatric case notes and the present physician's case notes were analyzed retrospectively. Socio-demographic data were compared to data derived from the annual statistics of the city of Leipzig, Germany in 2008. RESULTS: seventy two transferred patients were identified and included in the study, 48 patients responded to the questionnaire, the data of 24 non-responders were analysed retrospectively. About 90% of the responding patients with PKU were satisfied with the current transition situation. However, they agreed to several suggestions of improvement. Most specifically an interdisciplinary appointment before the definite transfer to the adult clinics was asked for. At the time of transition, most of the patients were in good metabolic control according to current treatment guidelines (median dried blood phenylalanine concentration 853 µmol/l before versus 690 µmol/l after transition). Of the interviewed patients 92% were still on a low phenylalanine diet in combination with the intake of a phenylalanine free amino acid mixture. Of the interviewees 77% carried a secondary school certificate or a secondary modern school qualification, but only 19% had achieved senior high school diploma (controls 38.2%). Marital status was comparable with the population of Leipzig. However, fewer patients with PKU had children (15% versus 37%). CONCLUSION: Transition of patients with PKU from pediatric to adult care seems to be successful in Leipzig. Patients were mostly satisfied with the transition situation. Still, some suggestions for improvements appeared to be desirable. During transition medical care and metabolic control were stable. However, with regard to psychosocial and socioeconomic data differences to the control population were detected.

Deletion and point mutations of PTHLH cause brachydactyly type E.

Autosomal-dominant brachydactyly type E (BDE) is a congenital limb malformation characterized by small hands and feet predominantly as a result of shortened metacarpals and metatarsals. In a large pedigree with BDE, short stature, and learning disabilities, we detected a microdeletion of approximately 900 kb encompassing PTHLH, the gene coding for parathyroid hormone related protein (PTHRP). PTHRP is known to regulate the balance between chondrocyte proliferation and the onset of hypertrophic differentiation during endochondral bone development. Inactivation of Pthrp in mice results in short-limbed dwarfism because of premature differentiation of chondrocyte. On the basis of our initial finding, we tested further individuals with BDE and short stature for mutations in PTHLH. We identified two missense (L44P and L60P), a nonstop (X178WextX( *)54), and a nonsense (K120X) mutation. The missense mutation L60P was tested in chicken micromass culture with the replication-competent avian sarcoma leukosis virus retroviral expression system and was shown to result in a loss of function. Thus, loss-of-function mutations in PTHLH cause BDE with short stature.

A case of maternal PKU syndrome despite intensive patient counseling.

We report on a 21-year-old woman with classic phenylketonuria, who presented at our outpatient clinic at week 14 of pregnancy. Despite intensive preconceptional counselling about the risk of raised Phenylalanine (Phe) levels for the offspring and nutritional consultations about the necessity to be on a Phe-restricted diet she had elevated blood Phe concentrations. Phe level could be lowered to the recommended range during a stay as an inpatient, but the patient was not able to maintain the recommended levels due to non-compliance. The patient delivered a newborn with classic maternal PKU syndrome (microcephaly, brachygnathia, congenital heart defect and psychomotoric retardation), which is nowadays rarely seen under preconceptional Phe-restricted diet. With more PKU patients reaching the childbearing age, intensive preconception counselling about maternal PKU syndrome is of pivotal importance for the women. However, a major factor in preventing Phe embryopathy is patient compliance in keeping the diet, which was insufficient in the case presented.

Three novel missense mutations within the LHX4 gene are associated with variable pituitary hormone deficiencies.

CONTEXT: The LHX4 LIM-homeodomain transcription factor has essential roles in pituitary gland and nervous system development. Heterozygous mutations in LHX4 are associated with combined pituitary hormone deficiency. OBJECTIVES: Our objectives were to determine the nature and frequency of LHX4 mutations in patients with pituitary hormone deficiency and to examine the functional outcomes of observed mutations. DESIGN: The LHX4 gene sequence was determined from patient DNA. The biochemical and gene regulatory properties of aberrant LHX4 proteins were characterized using structural predictions, pituitary gene transcription assays, and DNA binding experiments. PATIENTS: A total of 253 patients from 245 pedigrees with GH deficiency and deficiency of at least one additional pituitary hormone was included in the study. RESULTS: In five patients, three types of heterozygous missense mutations in LHX4 that result in substitution of conserved amino acids were identified. One substitution is between the LIM domains (R84C); the others are in the homeodomain (L190R; A210P). The patients have GH deficiency; some also display reductions in TSH, LH, FSH, or ACTH, and aberrant pituitary morphology. Structural models predict that the aberrant L190R and A210P LHX4 proteins would have impaired DNA binding and gene activation properties. Consistent with these models, EMSAs and transfection experiments using pituitary gene promoters demonstrate that whereas the R84C form has reduced activity, the L190R and A210P proteins are inactive. CONCLUSIONS: LHX4 mutations are a relatively rare cause of combined pituitary hormone deficiency. This report extends the range of phenotypes associated with LHX4 gene mutations and describes three novel exonic mutations in the gene.

PROP1 mutations cause progressive deterioration of anterior pituitary function including adrenal insufficiency: a longitudinal analysis.

Mutations in the PROP1 gene are the most frequent genetic defects in patients with combined pituitary hormone insufficiency. However, controversy exists about the timing and extent of pituitary insufficiency, and it remains unclear whether adrenal failure is a typical feature of this condition. We performed a retrospective longitudinal analysis of nine patients with PROP1 mutations who were under medical supervision at our clinic for 15.7 +/- 3.4 yr. All patients initially presented with growth failure (height sd score, -3.7 +/- 0.3) at a mean age of 4.9 +/- 0.8 yr. They were first diagnosed with GH and TSH deficiency, and replacement therapy was instituted at 6.1 +/- 1.1 and 6.8 +/- 1.2 yr, respectively. All seven patients who reached pubertal age required sex hormone substitution at 15.0 +/- 0.7 yr. Repeated functional testing of the anterior pituitary axes revealed a progressive decline with age in peak levels of GH, TSH, prolactin, and LH/FSH. All patients developed at least partial adrenal insufficiency, with a gradual decline of the function of the pituitary adrenal axis and eventually required substitution with hydrocortisone at a mean age of 18.4 +/- 3.5 yr. It is concluded that anterior pituitary function in patients with PROP1 mutations deteriorates progressively and includes adrenal insufficiency as a feature of this condition, which has important clinical relevance in childhood and adolescence.