Recognizing the tenascin-X deficient type of Ehlers-Danlos syndrome: a cross-sectional study in 17 patients.

The tenascin-X (TNX) deficient type Ehlers-Danlos syndrome (EDS) is similar to the classical type of EDS. Because of the limited awareness among geneticists and the challenge of the molecular analysis of the TNXB gene, the TNX-deficient type EDS is probably to be under diagnosed. We therefore performed an observational, cross-sectional study. History and physical examination were performed. Results of serum TNX measurements were collected and mutation analysis was performed by a combination of next-generation sequencing (NGS), Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA). Included were 17 patients of 11 families with autosomal recessive inheritance and childhood onset. All patients had hyperextensible skin without atrophic scarring. Hypermobility of the joints was observed in 16 of 17 patients. Deformities of the hands and feet were observed frequently. TNX serum level was tested and absent in 11 patients (seven families). Genetic testing was performed in all families; 12 different mutations were detected, most of which are suspected to lead to non-sense mRNA mediated decay. In short, patients with the TNX-deficient type EDS typically have generalized joint hypermobility, skin hyperextensibility and easy bruising. In contrast to the classical type, the inheritance pattern is autosomal recessive and atrophic scarring is absent. Molecular analysis of TNXB in a diagnostic setting is challenging.

Myopathy in a 20-year-old female patient with D4ST-1 deficient Ehlers-Danlos syndrome due to a homozygous CHST14 mutation.

We here report on a 20-year-old female patient with EDS due to a homozygous CHST14 single nucleotide deletion resulting in D4ST-1 deficiency, accompanied by muscle hypoplasia and muscle weakness. Findings of muscle ultrasound, electromyography, and muscle biopsy pointed to a myopathy, similarly as in other EDS types. This myopathy probably contributes to the gross motor developmental delay in this type of EDS.

Critical appraisal of the revised Ghent criteria for diagnosis of Marfan syndrome.

Marfan syndrome (MFS) is a connective tissue disorder with major features in cardiovascular, ocular and skeletal systems. Recently, diagnostic criteria were revised where more weight was given to the aortic root dilatation. We applied the revised Marfan nosology in an established adult Marfan population to define practical repercussions of novel criteria for clinical practice and individual patients. Out of 180 MFS patients, in 91% (n = 164) the diagnosis of MFS remained. Out of 16 patients with rejected diagnosis, four patients were diagnosed as MASS (myopia, mitral valve prolapse, borderline non-progressive aortic root dilatation, skeletal findings and striae) phenotype, three as ectopia lentis syndrome and in nine patients no alternative diagnosis was established. In 13 patients, the diagnosis was rejected because the Z-score of the aortic root was <2, although the aortic diameter was larger than 40 mm in six of them. In three other patients, the diagnosis of MFS was rejected because dural ectasia was given less weight in the revised nosology. Following the revised Marfan nosology, the diagnosis of MFS was rejected in 9% of patients, mostly because of the absence of aortic root dilatation defined as Z-score ≥2. Currently used Z-scores seem to underestimate aortic root dilatation, especially in patients with large body surface area (BSA). We recommend re-evaluation of criteria for aortic root involvement in adult patients with a suspected diagnosis of MFS.

Quality of life, developmental milestones, and self-esteem of young adults with congenital hypothyroidism diagnosed by neonatal screening.

CONTEXT: With advances in the treatment of congenital hypothyroidism (CH), the neuropsychological functioning of CH patients is considerably improved. Although much is written about cognitive and motor development, little is known about emotional and social consequences for patients growing up with CH, diagnosed by neonatal screening. OBJECTIVES: The objectives of the study were to: 1) compare health-related quality of life (HRQoL), developmental milestones also called course of life (CoL), sociodemographical outcomes, and self-esteem of CH patients with the general population; and 2) explore whether severity of CH was related to these outcomes. DESIGN/SETTING/PATIENTS: A total of 69 young adults with CH, born in The Netherlands in 1981-1982, completed the "TNO-AZL Questionnaire for Adult's Health related Quality of Life" questionnaire, the CoL survey (developmental milestones and sociodemographical outcomes), and a self-esteem questionnaire. MAIN OUTCOME MEASURES: HRQoL, CoL, social demographical outcomes, and self-esteem in young adults with CH were determined. RESULTS: CH patients are more often at risk for HRQoL impairment and reported lower HRQoL on several domains (cognitive functioning, P < 0.0001; sleeping, P < 0.004; pain, P < 0.0001; daily activities, P < 0.004; vitality, P < 0.0001; aggressiveness, P < 0.0001; and depressive moods, P < 0.0001) compared with healthy adults. Patients reported a lower self-esteem (P < 0.005) and had a delayed CoL on the domain of social development (P < 0.016). There were no significant within-group differences between the severity groups for HRQoL, CoL, and self-esteem. CONCLUSIONS: Negative consequences in terms of HRQoL, development, and self-esteem are prevalent in young adults with CH. Health care physicians should be attentive to these consequences and provide additional support (emotional and educational guidance) if necessary.

NGS panel analysis in 24 ectopia lentis patients; a clinically relevant test with a high diagnostic yield.

BACKGROUND: Several genetic causes of ectopia lentis (EL), with or without systemic features, are known. The differentiation between syndromic and isolated EL is crucial for further treatment, surveillance and counseling of patients and their relatives. Next generation sequencing (NGS) is a powerful tool enabling the simultaneous, highly-sensitive analysis of multiple target genes. OBJECTIVE: The aim of this study was to evaluate the diagnostic yield of our NGS panel in EL patients. Furthermore, we provide an overview of currently described mutations in ADAMTSL4, the main gene involved in isolated EL. METHODS: A NGS gene panel was analysed in 24 patients with EL. RESULTS: A genetic diagnosis was confirmed in 16 patients (67%). Of these, four (25%) had a heterozygous FBN1 mutation, 12 (75%) were homozygous or compound heterozygous for ADAMTSL4 mutations. The known European ADAMTSL4 founder mutation c.767_786del was most frequently detected. CONCLUSION: The diagnostic yield of our NGS panel was high. Causative mutations were exclusively identified in ADAMTSL4 and FBN1. With this approach the risk of misdiagnosis or delayed diagnosis can be reduced. The value and clinical implications of establishing a genetic diagnosis in patients with EL is corroborated by the description of two patients with an unexpected underlying genetic condition.

Neonatal screening for congenital hypothyroidism based on thyroxine, thyrotropin, and thyroxine-binding globulin measurement: potentials and pitfalls.

CONTEXT: The Dutch T(4)-TSH-TBG-based neonatal screening program detects patients with congenital hypothyroidism (CH) of thyroidal (CH-T) as well as central (CH-C) origin. The numbers and characteristics of true-positive and false-positive referrals will differ from other, predominantly TSH-based, screening methods. OBJECTIVE: The present study describes the characteristics of the referred neonates, both CH patients and false positives, and of the reported CH patients with a false-negative screening result born in the study period. DESIGN, SETTING, PATIENTS, AND MAIN OUTCOME MEASURE: For each referred child born between April 1, 2002, and May 31, 2004, screening results and first venous sample results were recorded and classified as transient or permanent CH-T or CH-C or as no CH. RESULTS: In the study period, 430,764 children were screened. Of the 772 children with abnormal screening results, 224 (29%) had CH; another 13 CH patients did not have abnormal screening results, giving an overall CH incidence of 1:1800. Incidences of permanent CH, permanent CH-T, permanent CH-C, and transient CH were 1:2200, 1:2500, 1:21,000, and 1:12,000, respectively. The most frequent explanations for the 548 false-positive referrals (71% of the referred cohort) were severe illness and TBG deficiency (occurring in 198 and 200 children, respectively). CONCLUSIONS: The Dutch incidence figures for CH belong to the highest worldwide, suggesting that the T(4)-TSH-TBG screening program is an efficient method to detect CH of variable etiology and severity. Still, a small percentage of children with CH escaped detection via this screening approach. Severe illness and TBG deficiency appear to be responsible for the majority of false-positive referrals.

Intellectual and motor development of young adults with congenital hypothyroidism diagnosed by neonatal screening.

CONTEXT: Long-term follow-up data on cognitive and motor functioning in adult patients with congenital hypothyroidism, diagnosed by neonatal screening, are scarce. Hence, it is still unclear whether the frequently reported cognitive and motor deficits observed during childhood persist in adulthood. OBJECTIVE: The objective of this study was to examine cognitive and motor functioning in young adults with congenital hypothyroidism, born in the first 2 yr after the introduction of the Dutch neonatal screening program. DESIGN/SETTING/PATIENTS: Seventy patients were tested (mean age, 21.5 yr); 49 of them were previously tested at 9.5 yr. The median age at the start of treatment was 28 d (range, 4-293 d). Congenital hypothyroidism was classified as severe, moderate, or mild, according to pretreatment T(4) concentrations. MAIN OUTCOME MEASUREMENT: The main outcome measurement was the influence of the severity of congenital hypothyroidism and age at which T(4) supplementation was started on cognitive and motor outcome. RESULTS: Patients, particularly those with severe congenital hypothyroidism, had significantly higher (i.e. worse) motor scores (total score, 7.8; ball skills, 2.0; balance, 4.1) compared with controls (total score, 3.2; ball skills, 0.7; balance, 1.1), and lower full-scale (95.8), verbal (96.4), and performance (95.6) intelligence quotient (IQ) scores than the normal population. No significant change in IQ from childhood to adulthood was found, and for the majority of patients, motor score classification remained the same. The severity of congenital hypothyroidism, but not the starting day of treatment, was correlated with IQ and motor scores. CONCLUSIONS: It is concluded that the severity of congenital hypothyroidism, but not the timing of treatment initiation, is an important factor determining long-term cognitive and motor outcome. Clearly, detrimental effects on developmental outcome in patients with congenital hypothyroidism persist over time.

The effect of life-long thyroxine treatment and physical activity on bone mineral density in young adult women with congenital hypothyroidism.

OBJECTIVE: Normalization of plasma thyrotropin in T4-supplemented patients with thyroidal congenital hypothyroidism (CH) requires elevated plasma FT4-concentrations compared to patients with acquired thyroidal hypothyroidism. We investigated bone mineral density (BMD) in patients with CH. PATIENTS AND METHODS: BMD was measured in 14 adult women with thyroidal CH and nine age-matched female controls. RESULTS: There were no significant differences between patients and controls for femoral neck bone mineral content (BMC) (38.6 vs 37.6 g), BMD (0.98 vs 1.01 g/cm(2)), T-score (0.1 vs 0.3 SD) and z-score (0.1 vs 0.3 SD) and for spine BMC (63.1 vs 71.9 g). The differences in spine BMD (0.97 vs 1.09 g/cm(2)), T-score (-0.7 vs 0.4 SD) and z-score (-0.5 vs 0.6 SD) were significant (p = 0.025, p = 0.023, and p = 0.021, respectively). CONCLUSIONS: Although BMD in patients with CH was slightly lower compared to controls, all scores were within the reference range. This does not support the hypothesis that the upwards shifted plasma FT4-concentrations in patients treated for CH have a deleterious effect on BMD.

[Central congenital hypothyroidism due to Graves' disease in the mother]. / Centrale congenitale hypothyreoïdie door ziekte van Graves bij de moeder.

Two male twins were born at a gestational age of 30 weeks. Five days after delivery, the mother was diagnosed with Graves' disease. The thyroid function in the neonates was therefore evaluated, which led to the detection of central congenital hypothyroidism (central CHT), even though the neonatal CHT-screening had been reported to be normal. Both boys were treated with thyroxine up to the age of nine months. It was then established that their development had been uneventful. Maternal Graves' disease can, due to the presence of anti-thyroid stimulating hormone (TSH) receptor antibodies and the maternal use of anti-thyroid drugs, result in thyroid dysfunction in the neonate. Neonates born to mothers with Graves' disease are at risk of developing central CHT. This occurs especially in children of mothers who are not treated or are inadequately treated during pregnancy. In view of the importance of thyroid hormone for brain development, children with central CHT are at risk for neurodevelopmental problems if thyroid dysfunction is not detected and treated early. The Dutch screening for congenital hypothyroidism is based on thyroxine (T4), TSH and thyroid-binding globulin. This makes it possible to detect central CHT. However, in prematurely born infants this disease may be missed because in this subgroup, referral is only based on increased TSH levels, which may not be present.

Disturbance of the fetal thyroid hormone state has long-term consequences for treatment of thyroidal and central congenital hypothyroidism.

BACKGROUND: During T(4) supplementation of patients with thyroidal (primary) congenital hypothyroidism (CH) TSH concentrations are frequently elevated despite free T(4) (FT(4)) concentrations being well within the reference range. To examine the thyroid's regulatory system, we analyzed thyroid function determinants in children with congenital and acquired thyroid disorders and in controls. METHODS: Retrospectively, plasma FT(4), TSH, and T(3) concentrations were analyzed in T(4)-supplemented children aged 0.5-20.0 yr with thyroidal CH, central (secondary or tertiary) CH, or autoimmune thyroid disease and in control children with type 1 diabetes mellitus. RESULTS: When TSH was within the reference range (0.4-4.0 mU/liter), mean FT(4) in thyroidal CH [1.65 ng/dl; 95% confidence interval (CI), 1.62-1.67] was significantly higher than in autoimmune thyroid disease (1.15 ng/dl; 95% CI, 1.11-1.19) and diabetes (1.08 ng/dl; 95% CI, 1.06-1.10). In central CH, when TSH was less than or equal to 0.02 mU/liter, mean FT(4) was 1.27 ng/dl (95% CI, 1.24-1.29). When FT(4) was within the reference range (0.78-1.79 ng/dl), 43% of the TSH measurements in thyroidal CH were more than 4.0 mU/liter, compared with 18% in autoimmune thyroid disease and 0% in type 1 diabetes mellitus; in central CH, 95% of TSH measurements were less than 0.4 mU/liter. CONCLUSIONS: In T(4)-supplemented patients with thyroidal CH, when TSH concentrations are established within the reference range, FT(4) concentrations tend to be elevated, and vice versa. Because this phenomenon could not be observed in acquired thyroidal hypothyroidism, we hypothesize that a pre- and/or perinatal hypothyroid state shifts the setpoint of the thyroid's regulatory system. In central CH, when FT(4) concentrations are established within the reference range, the pituitary secretes only minute amounts of TSH. For monitoring T(4) supplementation, reference ranges for FT(4) and TSH should be adapted to the etiology of hypothyroidism.

Idiopathic precocious puberty versus puberty in adopted children; auxological response to gonadotrophin-releasing hormone agonist treatment and final height.

OBJECTIVE: The objective of this study was to evaluate the characteristics of puberty and response to gonadotrophin-releasing hormone (GnRH) agonist treatment in adopted children compared with children with idiopathic precocious puberty (IPP). METHODS: We studied 17 girls with central IPP (group A) and 11 girls adopted from Asia and Central and South America (group B) with respect to auxological data at presentation of puberty and response to GnRH agonist treatment. RESULTS: In adopted girls, age at onset of puberty was later and duration of treatment was shorter. At the start of treatment, height-standard deviation score (H-SDS) was +1.67 s.d. in group A. In group B, H-SDS was comparably increased (+0.04 s.d.) assuming that the mean H-SDS in their native country is lower than the mean on the Dutch curve. During treatment, H-SDS decreased in both groups. Group A reached a final height (FH) of 166.2 cm (-0.3 s.d.) and group B of 156.1 cm (-1.9 s.d.). Predicted adult height (PAH) at the start of treatment underestimated FH in group A and overestimated FH in group B. At the end of treatment, PAH overestimated FH in both groups. The SDS for weight was above the mean in both groups at the start of treatment and increased even more during treatment. The age of occurrence of menses after treatment was stopped was the same in both groups (12.7 and 12.8 Years respectively). CONCLUSION: Despite the difference in timing of puberty between girls with IPP and adopted girls with early puberty, their response to treatment was similar in many aspects.

Can GnRH-agonist treatment cause slipped capital femoral epiphysis?

Slipped capital femoral epiphysis (SCFE) mainly occurs in pubertal children and is associated with delayed skeletal maturation, obesity, high growth velocity and tall stature. Furthermore, SCFE often coincides with endocrine disorders. This is the first report of a possible relationship between SCFE and GnRH agonist treatment: four patients developed SCFE during or shortly after treatment with GnRH agonists was stopped. We compared the clinical aspects of these patients with patients described in the literature who developed SCFE. Puberty started at the age of 3.3, 9.6, 0.0 and 5.6 years respectively. One patient developed sequential SCFE of both hips. SCFE occurred at the age of 11.9 (patient 1), 12.7 (patient 2), 14.3 (patient 2), 11.3 (patient 3) and 11.3 (patient 4) years. Of the five incidences of SCFE, one occurred during GnRH agonist treatment and four shortly after treatment was stopped. None of our patients met the typical criteria seen in SCFE and no 'regular' characteristics of patients with SCFE could be designated. Probably the hormonal changes during and shortly after treatment with GnRH agonists make the epiphysis more prone to slip. Considering our observations and by reviewing the literature, GnRH agonist treatment might present a risk factor for the occurrence of SCFE.

Splice site mutations in GH1 detected in previously (Genetically) undiagnosed families with congenital isolated growth hormone deficiency type II.

BACKGROUND: Congenital isolated growth hormone deficiency (IGHD) is a rare endocrine disorder that presents with severe proportionate growth failure. Dominant (type II) IGHD is usually caused by heterozygous mutations of GH1. The presentation of newly affected family members in 3 families with dominant IGHD in whom previous genetic testing had not demonstrated a GH1 mutation or had not been performed, prompted us to identify the underlying genetic cause. METHODS: GH1 was sequenced in 3 Caucasian families with a clinical autosomal dominant IGHD. RESULTS: All affected family members had severe growth hormone (GH) deficiency that became apparent in the first 2 years of life. GH treatment led to a marked increase in height SDS. So far, no other pituitary dysfunctions have become apparent. In the first family a novel splice site mutation in GH1 was identified (c.172-1G>C, IVS2-1G>C). In two other families a previously reported splice site mutation (c.291+1G>A, IVS3+1G>A) was found. CONCLUSION: These data show that several years after negative genetic testing it was now possible to make a genetic diagnosis in these families with a well-defined, clearly heritable, autosomal dominant IGHD. This underscores the importance of clinical and genetic follow-up in a multidisciplinary setting. It also shows that even without a positive family history, genetic testing should be considered if the phenotype is strongly suggestive for a genetic syndrome. Identification of pathogenic mutations, like these GH1 mutations, has important clinical implications for the surveillance and genetic counseling of patients and expands our knowledge on the genotype-phenotype correlation.

Homozygous and heterozygous expression of a novel mutation of the acid-labile subunit.

CONTEXT: Acid-labile subunit (ALS) deficiency due to homozygous inactivation of the ALS gene (IGFALS) is associated with moderate short stature, and in few cases pubertal delay. The clinical expression of heterozygosity is unknown. OBJECTIVE: To investigate the clinical, laboratory, and radiological features of homozygous and heterozygous carriers of a novel mutation in the ALS gene in comparison with non-carriers. SUBJECTS: Three short Kurdish brothers and their relatives. RESULTS: The index cases presented with short stature, microcephaly, and low circulating IGF-I and IGF-binding protein-3 (IGFBP-3), and undetectable ALS levels. Two were known with a low bone mineral density and one of them had suffered from two fractures. We found a novel homozygous ALS gene mutation resulting in a premature stop codon (c.1490dupT, p.Leu497PhefsX40). The IGF-I, IGFBP-3, and ALS 150 kDa ternary complex was absent, and ALS proteins in serum were not detected with western blot. IGFPB-1 and IGFPB-2 were low and there was a mild insulin resistance. Five heterozygous carriers tended to have a lower height and head circumference than five non-carriers, and had low plasma ALS and IGFBP-3 levels. Bone mineral (apparent) density was low in two out of three homozygous carriers, and also in four out of nine relatives. CONCLUSIONS: The clinical presentation of homozygous ALS mutations may, besides short stature, include microcephaly. Heterozygous carriers may have less statural and head growth, suggestive for a gene dosage effect.