Unusual presentation of familial glucocorticoid deficiency with a novel MRAP mutation

CONTEXT: Mutations in MRAP, an interacting partner of the ACTH receptor, have been shown recently to cause familial glucocorticoid deficiency (FGD) in kindreds with confirmed FGD and no ACTH receptor mutations. OBJECTIVE: We describe a Jewish-Ethiopian family with FGD caused by a novel MRAP mutation. PATIENTS: Our index patient presented at the age of 19 months with hypocortisolism, severe psychomotor retardation, myoclonic seizures, spastic quadriparesis, and microcephaly. Before the definite diagnosis was made, a female sibling was born in another hospital and succumbed during the neonatal period due to sepsis and adrenal crisis. METHODS: DNA was extracted from peripheral blood samples from the index case and his mother and from fibroblasts obtained from the female patient. The DAX-1, ACTH receptor (MC2R), and MRAP genes were analyzed. RESULTS: The index patient was diagnosed with FGD and was found to be homozygous for a novel MRAP mutation, a seven-base deletion in exon 3 of the MRAP gene. This deletion causes a frame shift, resulting in a stop codon after 23 amino acids (L31X). Postmortem analysis of fibroblasts obtained from the female patient revealed that she harbored the same mutation. CONCLUSIONS: This is the first report of MRAP mutations after the recent identification of the gene. Whether the novel MRAP mutation described by us is associated with a particularly severe phenotype remains to be investigated.     

Botulinum toxin injections for children with excessive drooling

The objective of this study was to evaluate the feasibility of ultrasonography-guided injections of botulinum toxin A into the parotid glands of children with severe drooling (sialorrhea). Excessive drooling is common in children with chronic neurologic disorders. Preliminary observations in adults suggest that injections of botulinum toxin A into the parotid glands can decrease drooling, but the optimal dose, sites of injection, and concomitant use of imaging during injections and its use for children have not been established. Ultrasonography was used to guide the injection of botulinum toxin (10-25 IU) into both parotid glands of nine children with excessive drooling. Subjective and objective measures of the severity of drooling were collected before and after botulinum toxin A injections. A booster injection was provided if the initial response was inadequate. Injections were well tolerated, and no adverse reactions were observed. Ultrasonography revealed that the parotid gland showed a variable depth, extent, and vascularization. Eight of nine patients needed a booster injection after 1 month. Objective measures of drooling severity were improved in seven of nine patients. However, subjective improvement was reported in only three of nine patients, and this improvement was functionally significant in only one patient. Although intraparotid injection of botulinum toxin A is safe and causes a reduction in saliva production in children, the doses used in this study did not result in functionally significant improvement. Higher doses of botulinum toxin A in the parotid glands or concomitant injections into the submandibular glands can increase the efficacy of these injections. Variability in size, depth, and vascular supply of the parotid gland suggests the importance of ultrasonography guidance for optimizing injections. These results underscore the need for further studies to establish the efficacy of this treatment in children.     

Identification of KIF21A mutations as a rare cause of congenital fibrosis of the extraocular muscles type 3 (CFEOM3)

PURPOSE: Three congenital fibrosis of the extraocular muscles phenotypes (CFEOM1-3) have been identified. Each represents a specific form of paralytic strabismus characterized by congenital restrictive ophthalmoplegia, often with accompanying ptosis. It has been demonstrated that CFEOM1 results from mutations in KIF21A and CFEOM2 from mutations in PHOX2A. This study was conducted to determine the incidence of KIF21A and PHOX2A mutations among individuals with the third CFEOM phenotype, CFEOM3. METHODS: All pedigrees and sporadic individuals with CFEOM3 in the authors' database were identified, whether the pedigrees were linked or consistent with linkage to the FEOM1, FEOM2, and/or FEOM3 loci was determined, and the appropriate pedigrees and the sporadic individuals were screened for mutations in KIF21A and PHOX2A. RESULTS: Twelve CFEOM3 pedigrees and 10 CFEOM3 sporadic individuals were identified in the database. The structures of eight of the pedigrees permitted the generation of meaningful linkage data. KIF21A was screened in 17 probands, and mutations were identified in two CFEOM3 pedigrees. One pedigree harbored a novel mutation (2841G-->A, M947I) and one harbored the most common and recurrent of the CFEOM1 mutations identified previously (2860C-->T, R954W). None of CFEOM3 pedigrees or sporadic individuals harbored mutations in PHOX2A. CONCLUSIONS: The results demonstrate that KIF21A mutations are a rare cause of CFEOM3 and that KIF21A mutations can be nonpenetrant. Although KIF21A is the first gene to be associated with CFEOM3, the results imply that mutations in the unidentified FEOM3 gene are the more common cause of this phenotype.     

Feasibility study of ultrasonic fatty liver biopsy: texture vs. attenuation and backscatter

The objective of this study was to compare textural to attenuation/backscatter indices of fatty liver correlated to histology to suggest the better approach for an objective noninvasive ultrasonic "biopsy". Forty-four patients with severe steatosis by histopathology were selected for this study. Ten patients had "pure" fatty liver and 34 had in addition fibrosis and/or inflammation. Ultrasonic images were acquired before needle insertion. The ROI used for biopsy was marked on the ultrasonic image and characterized by three attenuation/backscatter and 18 textural related indices. Statistical analysis was performed using logistic regression. Twenty-one healthy subjects served as control. The attenuation/backscatter indices were superior to textural indices in differentiating between the categories studied. Pure fatty livers could be reliably identified (AUC = 1, SE = 0). Among the 18 textural indices, "co-occurrences sum entropy" and "co-occurrences entropy" presented the best results. Attenuation/backscatter based indices appear to have better potential than the textural based indices.     

Peripheral neuropathy, episodic myoglobinuria, and respiratory failure in deficiency of the mitochondrial trifunctional protein

Mitochondrial trifunctional protein (TFP) deficiency is a rare disorder of the fatty acid beta-oxidation cycle with heterogeneous phenotypes and occurs secondary to either alpha- or beta-subunit mutations. We characterized the neuromyopathic phenotype of TFP deficiency through adolescence or adulthood in 11 patients, 8 with beta-subunit mutations and 3 with alpha-subunit mutations. Two independent clinical features occurred: infantile-onset progressive peripheral neuropathy and episodic exercise-, illness- or fasting-induced rhabdomyolysis accompanied by respiratory failure (in five patients). The combination of episodic rhabdomyolysis and peripheral neuropathy occurred in 10 of the 11 patients. The neuromyopathic phenotype is common in TFP deficiency (11 of 27 families from our cohort). Therefore, this disorder must be considered in the differential diagnosis of progressive peripheral neuropathy with or without episodic myoglobinuria.     

Sulthiame in childhood epilepsy

BACKGROUND: Sulthiame is a central carbonic anhydrase inhibitor found to be effective for both partial and generalized seizures. It has been in use in some European countries and in Israel for over 30 years. The aim of the present study was to evaluate the efficacy and tolerability of sulthiame in childhood epilepsy by conducting a multicenter, retrospective study of patients who received this drug. METHODS: The charts of 125 consecutive epilepsy patients treated with sulthiame as monotherapy or add-on therapy were reviewed. RESULTS: Twenty-nine out of 39 patients with benign focal epilepsy of childhood became seizure-free. Total seizure control was also achieved in 17 of 42 patients with symptomatic, non-refractory localization-related epilepsy, and in all 10 cases with juvenile myoclonic epilepsy. Complete normalization of the EEG occurred in 13 of 20 patients with benign partial epilepy of childhood. Side-effects were minimal and caused discontinuation of treatment in only seven children. CONCLUSION: The high tolerability, efficacy, convenience of use and low cost suggest that sulthiame should become a first line drug in the benign partial epilepsies of childhood and juvenile myoclonic epilepsy. It also has a role as add-on treatment in other partial and myoclonic epilepsies.     

Chorioangiomas of the placenta: sonographic and Doppler flow characteristics.

OBJECTIVE: To evaluate our experience with sonography and color Doppler blood flow in the diagnosis and management of chorioangiomas of the placenta. METHODS: All cases with placental chorioangiomas diagnosed in our sonography unit between 1992 and 2001 were included in the study. Sonographic and color Doppler flow characteristics were evaluated in all cases. Our cases were compared with all cases of placental chorioangiomas diagnosed antenatally by sonography published in the English literature between 1978 and 2001. RESULTS: Six cases of placental chorioangioma were identified antenatally, with a mean size of 6.5 cm (range, 4-13 cm). With the use of color Doppler flow, all cases of chorioangioma were shown to have either abundant blood flow or a large feeding vessel within the tumor. During follow-up, 2 cases had reduction of the intratumoral blood flow, and the outcomes were favorable. Three of our cases had delivery before 33 weeks' gestation (1 with intrauterine fetal death and 1 with termination of pregnancy). Review of the literature revealed 72 cases of antenatally diagnosed placental chorioangioma. Two thirds of the cases had dismal outcomes. CONCLUSIONS: The sonographic diagnosis of chorioangiomas of the placenta is feasible and necessitates close surveillance of these pregnancies because of the dismal prognosis in more than half. The addition of color Doppler flow is important in the diagnosis and antenatal follow-up of these pregnancies.     

Mutational analysis of PTEN/PIK3CA/AKT pathway in oral squamous cell carcinoma

The phosphoinositide 3-kinase (PI3K)/v-akt murine thymoma (AKT) viral oncogene pathway is involved in regulating the signaling of multiple biological processes such as apoptosis, metabolism, cell proliferation, and cell growth. Mutations in the genes associated with the PI3K/AKT pathway including PI3K, AKT, RAS and PTEN, are infrequently found within head and neck squamous cell carcinoma and more specifically are rarely reported in oral squamous cell carcinoma (OSCC) cases. We aimed to investigate the frequency of mutations in AKT1, PTEN, PIK3CA, and RAS (K-RAS, N-RAS, H-RAS) genes in 37 cases of oral squamous cell carcinoma (OSCC). Mutational analysis of PTEN, RAS, PIK3CA and AKT genes was performed using chip-based matrix-assisted laser desorption time-of-flight (MALDI-TOF) mass spectrometry and by direct sequencing. The only gene mutated in our series was the PIK3CA. Missense mutations of the PIK3CA gene were found in 4 of our cases (10.8%); no correlation has been found with oral location, stage and survival. The absence of mutations in AKT1, PTEN, and RAS genes in the present study is in accordance with previous studies confirming that these genes are rarely mutated in OSCC. Our data confirm that PIK3CA is important to OSCC tumorigenesis and can contribute to oncogene activation of the PIK3CA/AKT pathway in OSCC. The knowledge of the PIK3CA's involvement in OSCC is important because a specific kinase inhibitor could be considered as a future therapeutic option for OSCC patients with PIK3CA mutations.