Fryns syndrome in a girl born to consanguineous parents

An overweight female newborn with multiple congenital anomalies died shortly after birth. The parents were cousins. The following abnormal findings were noted: Broad, square-shaped head with flat nose, misshapen ears, cleft palate, receding chin, short neck with additional skinfolds, disproportionately short limbs, transverse palmar creases, distal digital hypoplasia with hypoplastic finger- and toenails. Autopsy disclosed a number of further malformations including: dysplasia of the hippocampus, atypical lobation of the lungs with cystic-adenomatoid malformation of the left upper lobe, malrotation of the intestine, bilateral cystic renal dysplasia, bilateral atretic ureters plus a right accessory hydroureter, hypoplastic urinary bladder, uterus and vagina duplex and elongated, partly cystic ovaries. The pattern of malformations in this girl is very similar to that of 7 previously reported patients including two sets of siblings and one instance of parental consanguinity. All patients died shortly after birth. For proper genetic counselling and for prenatal ultrasonographic diagnosis in a further pregnancy, it is important to recognize patients with the Fryns syndrome.     

Sicilian family with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) and lethal lung disease in one of the affected brothers

Introduction  We report the clinical and immunological features of the autoimmune regulator gene (AIRE) in two Sicilian brothers with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). They were compound heterozygotes with R203X/R257X. Both had oral candidiasis since the first year of life and later developed hypoparathyroidism and Addison disease. The elder brother had experienced recurrent lower respiratory infections since 5 years of age and over the years developed severe obstructive lung disease with bronchiectasis, which led to death at 18 years of age. Both brothers had circulating autoantibodies against tryptophan hydroxylase and serotonin-producing cells were absent in the duodenal mucosa. This was associated with intestinal dysfunction in only the elder brother. Conclusion  (1) In the first Sicilian family with APECED reported up to now we found a heterozygous mutation that had been previously reported only once. (2) In the older brother of this family we observed a severe and lethal lung disease; this case adds to a growing literature describing this association between APECED and respiratory illnesses. (3) Tryptophan hydroxylase antibodies might be hypothesized to be the marker of an autoimmune gastrointestinal illness possibly associated with APECED.     

自身免疫性多腺体病综合征ⅢD型1例

患儿,女,15.5岁,因视物模糊3月余,脱发、左膝关节疼痛1月余,面色苍白1d入院.患儿同时伴口腔黏膜疼痛、头晕、乏力、口干、眼干、皮肤干燥,无发热、头痛、腹痛、呕吐、胸闷、气促、皮疹、血尿及黑便.体查:T 36.5℃,P 98次/min,R 20次/min,BP 98/55 mm Hg,身高147 cm,体重44 kg,慢性病容,面色、口唇及甲床苍白,背部皮肤干燥可见少量脱屑,全身未见皮疹和水肿,浅表淋巴结和甲状腺未扪及,右侧颊黏膜可见一白色浅溃疡,双膝关节疼痛,无红肿、活动障碍及畸形,余无异常.血常规:白细胞3.8×109/L,中性粒细胞0.48,红细胞2.29×1012/L,血红蛋白73 g/L,网织红细胞0.85％,血小板159×109,C反应蛋白＜ 1.0 mg/L.     

Ectopic ACTH syndrome due to thymic carcinoid tumor in a girl.

An 8 year-old girl had a cushingoid appearance for six months. Hormone study showed extremely high serum levels of cortisol (> 60 micrograms/dl) and adrenocorticotropic hormone (930 pg/ml). Initial chest X-ray showed nothing unusual, but a technetium-99mm MIBI scan showed an accumulation lesion in the left upper chest cavity. Chest magnetic resonance imaging demonstrated that the mass was in the superior anterior mediastinum. She had complete removal of the tumor with partial thymectomy. The pathology revealed a thymic carcinoid tumor. Carcinoid tumors of the thymus are extremely rare in children and they usually present with Cushing's syndrome. To our knowledge, this is the youngest patient who has ever been reported with this disease.     

Autoimmune involvement in Cushing syndrome due to primary adrenocortical nodular dysplasia

Cushing syndrome due to primary adrenocortical nodular dysplasia was diagnosed in two patients, aged 3 years 9 months and 9.5 years. Subsequently, adrenalectomy was performed and followed by steroid replacement. In both cases, the adrenals were normal or only slightly enlarged and showed adrenocortical nodular dysplasia histologically. Small lymphocytic infiltrates consisting of T-cells and class II MHC positive macrophages were present in adrenal specimens of both the patients. Samples of protein A sepharose purified serum immunoglobulins from both children stimulated adrenocortical DNA synthesis and cortisol production in cultured guinea-pig adrenal segments in vitro in a dose dependent fashion. Adrenal stimulating immunoglobulins were also demonstrated in serum specimens of both patients' mothers. However, none of them had overt signs of adrenal disease. Our data support the view that autoimmune mechanisms may be involved in primary adrenocortical nodular dysplasia.     

Fatal liver failure due to ketoconazole treatment of a girl with Cushing's syndrome

A patient is reported who developed fatal liver failure on ketoconazole treatment for Cushing's syndrome. It is recommended that metyrapone be used when hypercortisolism has to be controlled as a temporary measure in childhood and adolescence.     

A novel mutation of the growth hormone receptor gene (GHR) in a Chinese girl with Laron syndrome

Laron syndrome, also known as growth hormone insensitivity syndrome (GHIS), is an autosomal recessive genetic disorder associated with severe postnatal growth failure, and normal and/or elevated growth hormone. This disease is frequently caused by a point mutation in the growth hormone receptor gene (GHR). Here, we identified a novel homozygous substitution mutation (E42K: GAG-->AAG at codon 42 cDNA) of the GHR gene in a Chinese girl with Laron syndrome. This mutation was predicted to impair the GHR binding affinity to human growth hormone (hGH), and was responsible for low levels of insulin-like growth factor (IGF)-I, IGF binding protein (IGFBP)-3, and GH binding protein (GHBP) in serum.     

Drug-induced enterocolitis syndrome (DIES) in a 10-year-old girl

We report the case of a child presenting with an adverse drug reaction highly suggestive of drug-induced enterocolitis syndrome (DIES) to amoxicillin (AMX). A 10-year-old girl developed repetitive vomiting and pallor without cutaneous or respiratory symptoms 2 h after AMX intake. DIES is not a well-described entity, and very few data are available in the literature. In the absence of an existing definition, the diagnosis of DIES can only be suspected and is based on its homology with food protein-induced enterocolitis (FPIES). The major criterion is the recurrence of repetitive and often incoercible vomiting occurring within 1–4 h of ingestion of the culprit food in the absence of IgE-mediated allergic classic skin and respiratory symptoms. Once the diagnosis of DIES to AMX is suspected, an open challenge with AMX should be undertaken with caution, under medical supervision in a day hospital unit because of the risk of severe recurrence. Once the diagnosis is confirmed, AMX should be contraindicated to avoid severe reactions.     

Persistent hyperinsulinemic hypoglycemia of infancy due to homozygous KCNJ11 (T294M) mutation

Hyperinsulinemic hypoglycemia is the most common cause of persistent hypoglycemia in infancy. While most of the cases are sporadic more than 100 mutations have been reported in the familial type. The authors report a case of familial hyperinsulinemic hypoglycemia with homozygous T294M mutation of the KCNJ11 gene, which responded to diazoxide therapy.     

Fatal fulminant hypereosinophilic syndrome with a petechial rash in a 16-year-old girl

Peripheral blood eosinophilia and eosinophilic tissue infiltration characterize the hypereosinophilic syndrome, which if untreated can be fatal. Its manifestations are protean. Often a diagnosis of exclusion, it presents diagnostic challenges. A fatal case of hypereosinophilic syndrome in a 16-year-old girl with petechiae, edema, urticaria, and diffuse erythema unfolded over 2 weeks. The histopathology of the petechiae demonstrated an eosinophilic and mixed cell interstitial and perivascular infiltrate and microthrombi in vessels. There was no evidence of T-cell clonality. Despite treatment with cyclosporine and methylprednisolone, she died. The age group; fulminant, fatal course without neoplasia; striking eosinophilia; and petechial rash are notable.     

Cerebellar atrophy without cerebellar cortex hyperintensity in infantile neuroaxonal dystrophy (INAD) due to PLA2G6 mutation.

Infantile neuroaxonal dystrophy (INAD) is a rare neurodegenerative disorder characterized by infantile onset and rapid progression of psychomotor regression and hypotonia evolving into spasticity. The neuroradiologic hallmark of the disease is represented by cerebellar atrophy and signal hyperintensity in the cerebellar cortex on MR T2-weighted images. We report a 2-year-old boy with psychomotor regression and hypotonia carrying a homozygous 5' splice site mutation in PLA2G6 gene, whose brain MRI revealed cerebellar atrophy with normal cerebellar cortex signal intensity. The absence of the signal hyperintensity of the cerebellar cortex does not rule out the diagnosis of INAD.     

Incipient spinal cord compression syndrome due to a herniation of calcified intervertebral disk in a young girl

Intervertebral disc calcification in childhood is rare. Calcifications are discovered by occasion during routine examinations of healthy children or evoke symptoms like neck and shoulder pain or discrete neurological symptoms. The prognosis of nearly all patients is excellent. We report on a 11-year-old girl, who suffered from acute pain in the neck and the left shoulder with increasing paresthesias of her left extremities which led to hospitalisation. Intervertebral disc calcifications were found between several cervical and thoracic vertebra. The only paraclinical finding was an elevated erythrocyte sedimentation rate. After 12 days of conservative and analgetic treatment the clinical condition deteriorated with acute worsening of the neck pain. The MRI revealed a posterior herniation of a calcified disc between the lower cervical spine with spinal cord compression. Immediate neurosurgical intervention led to decompression and disappearance of the symptoms. After 14 months the clinically healthy child only showed the persistence of one intervertebral disc calcification and a complete resolution of the former findings.     

Autoimmune hepatitis in a child presenting with hepatopulmonary syndrome (HPS)

HPS has been described in 9–20% of children with end‐stage liver disease. We present a case of a previously, asymptomatic nine‐yr‐old incidentally found to have low oxygen saturation. Physical exam was remarkable for digital clubbing, splenomegaly and orthodeoxia. Laboratory evaluation revealed a low platelet count, hyperammonemia, and prolonged coagulation studies. Sonography showed evidence of splenomegaly and portal venous hypertension. High resolution CT thorax and CTA were normal. HPS was confirmed by agitated saline contrast enhanced echocardiography and Tc‐99m MAA scan with evidence of intrapulmonary vascular dilatations. Liver biopsy was performed and consistent with autoimmune hepatitis. A high clinical index of suspicion should be maintained for HPS in pediatric patients who have unexplained hypoxemia as typical signs and symptoms of severe liver disease are often absent. In this report, we discuss a case of HPS complicated AIH in a pediatric patient and review the relevant literature.     

Delayed puberty due to a novel mutation in CHD7 causing CHARGE syndrome

We report the case of a 15-year-old girl who presented to a pediatric endocrinology clinic for delayed puberty with no signs of secondary sexual development. Her past medical history was significant for bilateral colobomas, inner-ear anomalies, hearing loss, and anosmia. Genetic testing revealed a novel de novo mutation in the CHD7 gene, one of the causative genes in CHARGE syndrome (coloboma, heart disease, choanal atresia, retarded growth and development and/or central nervous system anomalies, genital anomalies and/or hypogonadism, and ear anomalies and/or deafness). We review the distinction between hypogonadotrophic hypogonadism and hypergonadotrophic hypogonadism and discuss the availability of molecular genetic testing for idiopathic hypogonadotrophic hypogonadism. CHD7 mutations have also been found in some patients with Kallmann syndrome, hypogonadotrophic hypogonadism, and anosmia, and we discuss the overlap between this syndrome and CHARGE syndrome. With the increased availability of genetic testing for a variety of disorders, it is important for pediatricians to become familiar with interpreting genetic test results. Finally, we illustrate that Bayes' theorem is a useful statistical tool for interpreting novel missense mutations of unknown significance.     

Subclinical hyperthyroidism due to a thyrotropin receptor (TSHR) gene mutation (S505R)

AIM: To identify the molecular defect by which non-autoimmune subclinical hyperthyroidism was caused in a 6-mo-old infant who presented with weight loss. METHODS: Congenital non-autoimmune hyperthyroidism is caused by activating germline mutations in the thyrotropin receptor (TSHR) gene. Therefore, the TSHR gene was sequenced directly from the patient's genomic DNA. RESULTS: Molecular analysis revealed a heterozygous point mutation (S505R) in the TSHR gene as the underlying defect. CONCLUSION: A constitutively activating mutation in the TSHR gene has to be considered not only in patients with severe congenital non-autoimmune hyperthyroidism, but also in children with subclinical non-autoimmune hyperthyroidism.