Growth Failure Of Prenatal Onset Research Articles

RMRP-related short stature: A report of six additional Japanese individuals with cartilage hair hypoplasia and literature review.

Biallelic pathogenic variants in RMRP, the gene encoding the RNA component of RNase mitochondrial RNA processing enzyme complex, have been reported in individuals with cartilage hair hypoplasia (CHH). CHH is prevalent in Finnish and Amish populations due to a founder pathogenic variant, n.71A > G. Based on the manifestations in the Finnish and Amish individuals, the hallmarks of CHH are prenatal-onset growth failure, metaphyseal dysplasia, hair hypoplasia, immunodeficiency, and other extraskeletal manifestations. Herein, we report six Japanese individuals with CHH from four families. All probands presented with moderate short stature with mild metaphyseal dysplasia or brachydactyly. One of them had hair hypoplasia and the other immunodeficiency. By contrast, the affected siblings of two families showed only mild short stature. We also reviewed all previously reported 13 Japanese individuals. No n.71A > G allele was detected. The proportions of Japanese versus Finnish individuals were 0% versus 70% for birth length < -2.0 SD, 84% versus 100% for metaphyseal dysplasia and 26% versus 88% for hair hypoplasia. Milder manifestations in the Japanese individuals may be related to the difference of genotypes. The mildest form of CHH phenotypes is mild short stature without overt skeletal alteration or extraskeletal manifestation and can be termed "RMRP-related short stature".

Ciliopathy due to POC1A deficiency: clinical and metabolic features, and cellular modeling.

SOFT syndrome (MIM#614813), denoting Short stature, Onychodysplasia, Facial dysmorphism, and hypoTrichosis, is a rare primordial dwarfism syndrome caused by biallelic variants in POC1A, encoding a centriolar protein. SOFT syndrome, characterized by severe growth failure of prenatal onset and dysmorphic features, was recently associated with insulin resistance. This study aims to further explore its endocrinological features and pathophysiological mechanisms. We present clinical, biochemical, and genetic features of 2 unrelated patients carrying biallelic pathogenic POC1A variants. Cellular models of the disease were generated using patients' fibroblasts and POC1A-deleted human adipose stem cells. Both patients present with clinical features of SOFT syndrome, along with hyperinsulinemia, diabetes or glucose intolerance, hypertriglyceridemia, liver steatosis, and central fat distribution. They also display resistance to the effects of IGF-1. Cellular studies show that the lack of POC1A protein expression impairs ciliogenesis and adipocyte differentiation, induces cellular senescence, and leads to resistance to insulin and IGF-1. An altered subcellular localization of insulin receptors and, to a lesser extent, IGF1 receptors could also contribute to resistance to insulin and IGF1. Severe growth retardation, IGF-1 resistance, and centripetal fat repartition associated with insulin resistance-related metabolic abnormalities should be considered as typical features of SOFT syndrome caused by biallelic POC1A null variants. Adipocyte dysfunction and cellular senescence likely contribute to the metabolic consequences of POC1A deficiency. SOFT syndrome should be included within the group of monogenic ciliopathies with metabolic and adipose tissue involvement, which already encompasses Bardet-Biedl and Alström syndromes.

Growth and neurodevelopmental disorder with arthrogryposis, microcephaly and structural brain anomalies caused by Bi-allelic partial deletion of SMPD4 gene.

Neutral sphingomyelinases have an important role in generation of ceramide and phosphorylcholine from sphingomyelins which then act as secondary messengers in various signaling pathways of the cellular machinery. They function ubiquitously with a predominant role in the central nervous system. Neutral sphingomyelinase type 3, encoded by SMPD4 gene has recently been reported to cause a severe autosomal recessive neurodevelopmental disorder with congenital arthrogryposis and microcephaly. We report a 22-month-old girl having characteristic features of neurodevelopmental delay, prenatal onset growth failure, arthrogryposis, microcephaly and brain anomalies including severe hypomyelination, simplified gyral pattern and hypoplasia of corpus callosum and brainstem. Additionally, she was noted to have nystagmus and visual impairment secondary to macular dystrophy and retinal pigment epithelial stippling at posterior pole. Copy number variant analysis from trio whole exome sequencing (ES) enabled identification of a homozygous 11kb deletion encompassing exons 18 −20 of SMPD 4 gene, confirming the diagnosis of SMPD4-related disorder in her.

Giant choroid plexus papilloma in Mulibrey nanism syndrome

Mulibrey (muscle, liver, brain, eye) nanism (MUL) is an autosomal recessive disorder caused by mutations in the TRIM37 gene encoding a protein of unknown function. MUL is characterized by progressive growth failure of prenatal onset, tri- angular face with hydrocephaloid skull, general thinness and muscular hypotonicity, peculiar voice, venous congestion caused by pericardial constriction, and pigment dispersion and yellowish dots in ocular fundi. Many studies in MUL patients showed that MUL is associated with frequent malignant tumors, benign adenomas and vascular lesions. Generally, MUL patients are consid- ered neurologically normal. Up to today, several arachnoidal cysts have been demonstrated in MUL patients. A nodular lesion of the plexus choroideus has been detected only in one MUL patient. Thus, choroid plexus papilloma has never been demonstrated in MUL patients. Our patient is an unusual example of MUL with giant choroid plexus papilloma and the first case in literature.

High frequency of tumours in Mulibrey nanism

Mulibrey nanism (MUL) is a monogenic disorder with prenatal-onset growth failure, typical clinical characteristics, cardiopathy and tendency for a metabolic syndrome. It is caused by recessive mutations in the TRIM37 gene encoding for the peroxisomal TRIM37 protein with ubiquitin-ligase activity. In this work, the frequency and pathology of malignant and benign tumours were analysed in a national cohort of 89 Finnish MUL patients aged 0.7-76 years. The subjects had a clinical and radiological evaluation, and histological and immunohistocemical analyses on specimens obtained from biopsy, surgery or autopsy, were performed. The results show that the MUL patients have disturbed architecture with ectopic tissues and a high frequency of both benign and malignant tumours detectable in several internal organs. A total of 210 tumorous lesions were detected in 66/89 patients (74%). Fifteen malignancies occurred in 13 patients (15%), seven of them in the kidney (five Wilms' tumours), three in the thyroid gland, two gynaecological cancers, one gastrointestinal carcinoid tumour, one neuropituitary Langerhans cell histiocytosis and one case of acute lymphoblastic leukaemia (ALL). Tumours detected by radiology in the liver and other organs mainly comprised strongly dilated blood vessels (peliosis), vascularized cysts and nodular lesions. The lesions showed strong expression of the endothelial cell markers CD34 and CD31 as well as the myocyte marker alpha-smooth muscle actin (alpha-SMA). Our findings show that MUL is associated with frequent malignant tumours and benign adenomatous and vascular lesions, as well as disturbed organ development.

Characterisation of the mulibrey nanism-associated TRIM37 gene: Transcription initiation, promoter region and alternative splicing

The TRIM37 gene encodes a peroxisomal protein of unknown function. Mutations in TRIM37 underlie mulibrey nanism, a rare autosomal recessively inherited disorder with severe growth failure of prenatal onset, constrictive pericardium, hepatomegaly and characteristic dysmorphic features. Eleven mulibrey nanism-associated mutations have been identified. We here characterised TRIM37 further by mapping the transcription initiation site and promoter region as well as by analysing splice variants. By primer extension analysis, several transcription initiation sites were localised to a region between − 246 and − 373 relative to the ATG codon for translation initiation. Basal promoter activity was mapped within 600 nucleotides upstream from the translation initiation site using promoter-luciferase reporter constructs. Several alternative splice variants of TRIM37 exist in databases. Most of these predict non-functional protein products, are expressed at low levels and are thus likely to be targets for nonsense-mediated mRNA decay. A novel splice variant, TRIM37b, with an alternative termination codon and 3′untranslated region (UTR) transcribed from an exon 16 kb downstream from exon 24, predicts an identical protein product with the previously identified transcript, TRIM37a. As seen by Northern blot analysis and quantitative real-time PCR, both transcripts are highly expressed in testis, whereas in other tissues TRIM37a is prominent. The 3′UTR of the PPM1E gene in the opposite strand overlaps TRIM37b. These data suggest that TRIM37 expression is regulated by several mechanisms: through nonsense surveillance of non-functional transcripts, as well as through 3′UTR regulatory sequences and/or naturally occurring antisense RNAs especially in testis.

Insulin Resistance Syndrome in Subjects With Mutated RING Finger Protein TRIM37

We evaluated the glucose and lipid metabolism in 65 patients (aged 1.1-55 years) with mulibrey (muscle-liver-brain-eye) nanism (MUL), which is a monogenic disorder with prenatal-onset growth failure and typical clinical characteristics. MUL is caused by mutations in the TRIM37 gene, encoding a peroxisomal protein (TRIM37) with E3 ubiquitin-ligase activity. The subjects underwent clinical evaluation, abdominal ultrasonography, and laboratory measurements, including a 3-h oral glucose tolerance test. The results showed a dramatic change in glucose and lipid metabolism with age in MUL subjects. While the children had low fasting glucose and insulin levels, 90% of the adults had high fasting and postload insulin values (up to 1,450 mU/l). A 10-fold decrease in the fasting glucose-to-insulin ratio and a 4-fold decrease in whole-body insulin sensitivity index were observed. Insulin resistance, fatty liver, high serum leptin, hypertension, and acantosis nigricans were already evident in many slim prepubertal children. Half of the adults had type 2 diabetes, and an additional 42% showed impaired glucose tolerance. Seventy percent fulfilled the National Cholesterol Education Program criteria for metabolic syndrome. The peroxisomal targeting and the functional link of TRIM37 to the ubiquitin-proteosome pathway may provide novel clues to the development of metabolic syndrome.

Gene encoding a new RING-B-box-Coiled-coil protein is mutated in mulibrey nanism.

Mulibrey nanism (for muscle-liver-brain-eye nanism, MUL; MIM 253250) is an autosomal recessive disorder that involves several tissues of mesodermal origin, implying a defect in a highly pleiotropic gene. Characteristic features include severe growth failure of prenatal onset and constrictive pericardium with consequent hepatomegaly. In addition, muscle hypotonia, J-shaped sella turcica, yellowish dots in the ocular fundi, typical dysmorphic features and hypoplasia of various endocrine glands causing hormonal deficiency are common. About 4% of MUL patients develop Wilms' tumour. MUL is enriched in the Finnish population, but is rare elsewhere. We previously assigned MUL to chromosome 17q22-q23 and constructed a physical contig over the critical MUL region. The region has now been further refined by haplotype analysis and new positional candidate genes have been localized. We identified a gene with four independent MUL-associated mutations that all cause a frameshift and predict a truncated protein. MUL is ubiquitously expressed and encodes a new member of the RING-B-box-Coiled-coil (RBCC) family of zinc-finger proteins, whose members are involved in diverse cellular functions such as developmental patterning and oncogenesis.

A syndrome of primary combined immunodeficiency with microcephaly, cerebellar hypoplasia, growth failure and progressive pancytopenia

A male infant with primary combined immunodeficiency, microcephaly with marked cerebellar hypoplasia, and growth failure of prenatal onset is presented. He developed progressive pancytopenia in the 3rd year of life and died at 42 months from disseminated aspergillosis. Laboratory studies and post mortem examination failed to reveal any known aetiology for his disorder. Hreidarsson et al. [3] previously described a syndrome of progressive pancytopenia with microcephaly, cerebellar hypoplasia and growth failure in three boys, with similar clinical and laboratory findings. Although extensive immunological investigations were not performed in those previous patients, recurrent infections in two of them are suggestive of immunodeficiency. In the light of the immunological findings in our patient, we propose that the condition of the four patients belongs to the same syndrome, which has to be considered as a primary combined immunodeficiency syndrome. This syndrome can be distinguished from the other known immunodeficiency syndromes by its associated characteristic features, namely microcephaly with cerebellar hypoplasia, growth failure of prenatal onset and progressive pancytopenia.

A Syndrome of Progressive Pancytopenia with Microcephaly, Cerebellar Hypoplasia and Growth Failure

A male infant with congenital thrombocytopenia, progressing to pancytopenia in the second year of life is presented. Other findings included microcephaly with cerebellar hypoplasia, growth failure of prenatal onset and severe psychomotor retardation. He died at 23 months of age from candida albicans septicemia. Laboratory studies and a postmortem examination failed to reveal any known etiology for his disorder, but parental consanguinity suggests a genetic basis with an autosomal recessive mode of inheritance. Høyeraal et al. have previously reported two brothers with similar clinical and laboratory findings. It is proposed that the condition of these three patients should be considered as a separate syndrome of congenital pancytopenia, distinguished from other congenital myeloid dysplasias by the extramedullary findings.

MULIBREY NANISM, AN AUTOSOMAL RECESSIVE SYNDROME WITH OCULAR INVOLVEMENT

Mulibrey nanism is a rare autosomal recessive condition characterized by a growth failure of pre-natal onset and several associated dysmorphic features. On ophthalmoscopy the optic disc and macula have a normal appearance while the midperiphery and more peripheral areas have revealed hypopigmentation and pigment scattering. By fluorescein angiography areas of focal choroidal hypoplasia have been noted. Histopathological examination of a typical case revealed atrophy of the corneal epithelium and thickening of the Bowman's membrane. The optic nerve and the macula appeared normal while the midperiphery showed focal choroidal hypoplasia with marked atrophy of the retina and of the pigment epithelium. Occasional drusen were also noted in this area. The findings do confirm the hypothesis that the choroidal changes represent one further manifestation originating from mesodermal tissues in these patients.

Urinary cyclic adenosine 3′, 5′-monophosphate excretion in children of short stature: Effect of somatotropin

Excretion of urinary cyclic adenosine 3',5'-monophosphate (cAMP) was determined in twenty-four children of short stature and in sixteen normal children. Of the patients, eight suffered from anterior panhypopituitarism, six from isolated deficiency or somatotropin, seven had a family history of short stature, and three had growth failure of pre-natal onset. In children suffering from anterior panhypopituitarism or from isolated somatotropin deficiency, excretion of cAMP was found to be depressed. Short-term administration of purified somatotropin in normal therapeutic dose (3.4 mg per 1.7 m2 i.m. daily for 5 days) had no effect on urinary cAMP, but reduced urine volume in all patient groups. During somatotropin treatment there was a positive correlation between changes in urine volume and nitrogen balance (r = 0.67).

Nitrogen (N) balance and calorie efficiency in growth failure of prenatal onset

Nitrogen (N) balance and calorie efficiency in growth failure of prenatal onset

BMR, DNA AND CELL SIZE IN PRE- AND POSTNATALLY DEPRIVED RATS

In Infants BMRs are lower In prenatal than in postnatal onset growth failure. The significance of this was Investigated In rats with similar types of growth failure by relating their BMR to body velght (BWt), combined organ (O: liver, kidney, heart, and brain) weight (OWt), DNA (ODNA), and protein (OPr). Mature rats were fed a 6% protein diet 1 month prior to and during mating, gestation, and lactation. Offsprings were fed 27% protein at weaning (A). Offsprings of normal rats were fed low protein from weaning to 10 weeks and high protein up to weight recovery (6). The Insult caused permanent stunting In group A rats; ¾ of group B rats had normal weights by 24 weeks. Sleeping BMRs were measured In 4 rats of each group before sacrificing, at weaning, 10, 16, and >16 weeks, and in litter-mates weekly up to maturity. The relation of the BMR with BWt, OWt, and OPr was curvl-linear; that with ODNA was linear. These relations were similar for normal controls. The BMR per BWt, OWt, and OPr decreased with age as cell size Increased. The insults affected ODNA and OPr of liver, kidney, and heart in both groups but not of brain. Recovery paralleled weight recovery. Recovery of cell size occurred first. The data show that the BMR reflects cell number rather than cell mass. Comparison of the BMRs suggests that the Insult of group A rats was not comparable to that which caused dwarfing In Infants with growth failure of prenatal onset.