Clinical and molecular evaluation of 13 Brazilian patients with Gomez-López-Hernández syndrome.

We aim to characterize patients with Gomez-López-Hernández syndrome (GLHS) clinically and to investigate them molecularly. A clinical protocol, including a morphological and neuropsychological assessment, was applied to 13 patients with GLHS. Single-nucleotide polymorphism (SNP) array and whole-exome sequencing were undertaken; magnetic resonance imaging was performed in 12 patients, including high-resolution, heavily T2-weighted sequences (HRT2) in 6 patients to analyze the trigeminal nerves. All patients presented alopecia; two did not present rhombencephalosynapsis (RES); trigeminal anesthesia was present in 5 of the 11 patients (45.4%); brachycephaly/brachyturricephaly and mid-face retrusion were found in 84.6 and 92.3% of the patients, respectively. One patient had intellectual disability. HRT2 sequences showed trigeminal nerve hypoplasia in four of the six patients; all four had clinical signs of trigeminal anesthesia. No common candidate gene was found to explain GLHS phenotype. RES does not seem to be an obligatory finding in respect of GLHS diagnosis. We propose that a diagnosis of GLHS should be considered in patients with at least two of the following criteria: focal non-scarring alopecia, rhombencephalosynapsis, craniofacial anomalies (brachyturrycephaly, brachycephaly or mid-face retrusion), trigeminal anesthesia or anatomic abnormalities of the trigeminal nerve. Studies focusing on germline whole genome sequencing or DNA and/or RNA sequencing of the alopecia tissue may be the next step for the better understanding of GLHS etiology.

Gomez-López-Hernández syndrome: A case report with clinical and molecular evaluation and literature review.

Gomez-López-Hernández syndrome (GLHS) is characterized by rhombencephalosynapsis (RES), alopecia, trigeminal anesthesia and a distinctive phenotype, including brachyturricephaly. It has been suggested that GLHS should be considered as part of the spectrum of RES-associated conditions that include alopecia, trigeminal anesthesia, and craniofacial anomalies, rather than a distinct entity. To the best of our knowledge, 57 patients with GLHS have been described. Despite its first description in 1979, the etiology of this syndrome remains unknown. Here, we describe, to our knowledge, the first case of a patient with GLHS who was molecularly evaluated and had been prenatally exposed to misoprostol. We also reviewed the clinical and morphological features of the patients described to date to better delineate the phenotype and focus on any evidence for adverse pregnancy outcomes or exposure, including teratogens.

Severe forms of Johanson-Blizzard syndrome caused by two novel compound heterozygous variants in UBR1: Clinical manifestations, imaging findings and molecular genetics.

Johanson-Blizzard Syndrome (JBS) is a rare autosomal recessive genetic disorder characterized by exocrine pancreatic insufficiency, distinct abnormal facial appearance and varying degrees of growth retardation. Variants in UBR1 gene are considered to be responsible for the syndrome. Here, we describe a 3-year old boy, who visited our clinic for severe growth retardation and frequent oily diarrhea. The physical examination revealed nasal alae aplasia, scalp defect, and maldescent of left testicle. Transabdominal ultrasound and computed tomography scan of his abdomen demonstrated complete fatty replacement of the pancreas. The clinical, laboratory, and imaging findings strongly suggest the diagnosis of hereditary pancreatitis. Whole exome sequencing revealed two rare compound heterozygous variants, c.2511T > G (p.H837Q) and c.1188T > G (p.Y396X), in the UBR1 gene of this boy, so, the diagnosis of JBS was established. This is the first report of Chinese patient with JBS, and our study indicates that transabdominal ultrasound and computed tomography are two useful and noninvasive imaging methods for the diagnosis and evaluation of JBS, and identification of these two novel variants expands the database of UBR1 gene variants. Furthermore, with the availability of the identification technology for these variants, prenatal diagnosis could be offered for future pregnancies.

Kosaki overgrowth syndrome: A newly identified entity caused by pathogenic variants in platelet-derived growth factor receptor-beta.

Specific classes of de novo heterozygous gain-of-function pathogenic variants of the PDGFRB (platelet-derived growth factor receptor-beta) cause a distinctive overgrowth syndrome, named the Kosaki overgrowth syndrome (KOGS) (OMIM #616592). Until now, six patients with this condition have been reported in the literature. In addition to skeletal overgrowth, these patients exhibit hyperelastic, translucent, and fragile skin, scoliosis, progressive loss of subcutaneous adipose tissue, skull deformity, infantile myofibromas, neuropsychiatric symptoms, and arachnoid cysts in the posterior fossa and periventricular white matter signal abnormalities on neuroimaging. This constellation of phenotypes clearly distinguishes KOGS from other PDGFRB-related disorders, including idiopathic basal ganglia calcification, infantile myofibroma, and Penttinen-type premature aging syndrome. From a molecular standpoint, PDGFRB is a dimeric receptor tyrosine kinase that plays critical roles in cell growth and tumorigenesis. The two known types of pathogenic variants (p.(Pro584Arg) and p.(Trp566Arg)) of the PDGFRB that cause KOGS are exclusively located in the juxtaglomerular domain that regulates autoactivation/inhibition of PDGFRB. In-vitro evidence suggests that p.(Pro584Arg) represents a gain-of-function pathogenic variant. Inhibition of PDGFRB activity using multi-kinase inhibitors appears to be a potentially promising therapeutic approach. Investigation of the molecular mechanisms underlying the pathogenesis of this disease using induced pluripotent stem cells is under way. Presence of skeletal overgrowth, distinctive facial features, characteristic hyperelastic and fragile skin, and cerebral white matter lesions with neuropsychiatric symptoms should prompt genetic analysis of the PDGFRB.

Quantitative three-dimensional assessment of Madelung deformity.

In the diagnostic work-up of Madelung deformity conventional radiographic imaging is often used, assessing the three-dimensional deformity in a two-dimensional manner. A three-dimensional approach could expand our understanding of Madelung deformity's complex wrist anatomy, while removing inter- and intra-rater differences. We measured previous two-dimensional-based and newly developed three-dimensional-based parameters in 18 patients with Madelung deformity (28 wrists) and 35 healthy participants (56 wrists). Madelung deformity wrists have increased levels of ulnar tilt, lunate subsidence, lunate fossa angle, and palmar carpal displacement. The lunate fossa is more concave and irregular, and angles between scaphoid, lunate, and triquetral bones are decreased. These findings validate the underlying principles of current two-dimensional criteria and reveal previously unknown anatomical abnormalities by utilizing novel three-dimensional parameters to quantify the radiocarpal joint.

Comparison of MRI with dedicated head and neck signal amplification coil and cone beam computed tomography: MRI is a useful tool in diagnostics of cranio-facial growth disorders.

OBJECTIVE: Magnetic resonance imaging (MRI) shows excellent image quality for the depiction of soft tissues and is therefore an important imaging technique in medical diagnostics. However, the practical simultaneous presentation of hard and soft tissue structures of the mouth, jaw and facial area is not fully satisfactory at this time. We investigated the image quality of 1.5 T MRI using a dedicated signal amplifying coil for the application in the oral and maxillofacial field of and compared it with cone beam computed tomography (CBCT). We hypothesized that imaging quality for growth disorders of the facial skull does not differ significantly between the two imaging techniques. MATERIALS AND METHODS: 12 patients were consecutively enrolled into this study between 01/2016 and 12/2017. Patients received diagnostic imaging for clinical indications using 1,5 T MRI using a dedicated head and neck coil for signal amplification as well as an CBCT. For each patient 5 different MRI sequences and one CBCT protocol were assessed. Images were evaluated by a radiologist and a dentist in consensus. On the basis of 51 anatomical structures and orthodontic, cephalometric reference points, the five datasets were subjectively rated and compared to the CBCT dataset. RESULTS: Patient age was in the range of 19-78 years. 2614 (69.8%) out of 3744 possible valuations were assessable. Compared to CBCT, MRI images were rated to have a superior image quality of presentation for 42 out of 51 anatomic structures (p < 0.05). Notably, 5 out of 51 structures were not assessable due to missing values. T1-weighted MRI images were rated superiorly to T2-weighted images in displaying anatomically relevant landmarks in the oral and maxillofacial field. MRI datasets were inferior in imaging cephalometric and orthodontic reference points in comparison to CBCT images. CONCLUSION: In conclusion, this pilot study demonstrates that radiation-free dental MRI enables a reliable detection of important anatomical structures. Thus, the signal amplified MRI presents a radiation-free imaging alternative to established CBCT in craniofacial growth disorders protocols. However, imaging quality in MRI datasets remains inferior to CBCT images for cephalometric and orthodontic reference points.

SHOX far-downstream copy-number variations involving cis-regulatory nucleotide variants in two sisters with Leri-Weill dyschondrosteosis.

SHOX haploinsufficiency leading to Leri-Weill dyschondrosteosis (LWD) and idiopathic short stature typically results from intragenic mutations or copy-number variations (CNVs) involving SHOX and/or its putative enhancer regions that are distributed in the genomic interval between 400 kb and 840 kb from Xpter/Ypter. Here, we report two sisters with LWD, who carried a deletion in the far-downstream region of SHOX. The 0.62 Mb deletion contained 50 single nucleotide polymorphisms (SNPs) and short insertions and deletions (indels), whose genotypes were linked to SHOX expression levels in the Genotype-Tissue Expression portal. Notably, most of these SNPs/indels accumulated within a ~20 kb interval that was positioned ~900 kb away from Xpter/Ypter. These SNPs/indels showed similar minor allele frequencies, indicating that they reside within a haplotype block. The ~20 kb interval was not evolutionarily conserved; however, it was associated with the previously determined peak of chromosome conformation capture profiling (4C)-seq. Importantly, the deletion in the present cases partially overlapped with CNVs of three previous cases with skeletal deformity and/or short stature. The results indicate that far-downstream CNVs constitute rare genetic causes of SHOX haploinsufficiency. These CNVs possibly impair SHOX expression through copy-number changes of a human-specific cis-regulatory haplotype block. This notion awaits further validation.

Imaging in Short Stature and Bone Age Estimation.

Short stature in children is a diagnostic challenge to the physician. Bone age assessment can be done using various methods. The causes of short stature are variable; often leading to a series of investigations. The endocrine conditions have typical imaging features. This chapter provides a short overview of the methods of bone age estimation, and imaging findings and algorithmic approach towards a child with short stature.

Madelung's deformity: capitate-related versus ulna-related measurement methods.

Several investigators have defined measurements for Madelung's deformity based on the distal radius or on the longitudinal ulnar axis to avoid the distorted distal radius and its lunate fossa. However, errors may occur in severe cases because of ulnar deformity and displacement. We quantified seven established measurements for Madelung's deformity relying on the central axis of the capitate. The inter- and intrarater reliability of the capitate-related and the ulna-related techniques were compared. We observed a higher inter- and intrarater reliability for the capitate-related method than for the ulna-related method. Better agreement was also observed for measurements of distance than for measurements of angles. However, the palmar tilt angle measurement method was neither reliable nor reproducible. The capitate-related technique can help to accurately determine the severity of Madelung's deformity, assist in surgical planning and identify the prognosis. Level of evidence: III.

MRI appearance of the anomalous volar radiotriquetral ligament in true Madelung deformity.

OBJECTIVE: To characterize the MRI appearance of the anomalous volar radiotriquetral ligament in cases of classic Madelung deformity. MATERIALS AND METHODS: With institutional review board approval, a search of the radiology information system was performed to identify cases of potential Madelung deformity using variations of the criteria "Madelung deformity." Cases of classic Madelung deformity were included based on the following criteria: dorsal subluxation of the ulnar head, volar tilt of the distal radius, increased radial inclination of greater than 25°, triangulation of the carpus, and presence of Vickers ligament defined as an anomalous volar radiolunate ligament. Patients with a history of wrist trauma or severe degenerative change distorting anatomy were excluded. The resulting cases were reviewed to characterize the anomalous radiotriquetral ligament. RESULTS: Eight cases of classic Madelung deformity in 6 patients were identified. All 8 cases were characterized by the presence of an anomalous radiotriquetral ligament, which was more conspicuous than Vickers ligament. None of the excluded pseudo-Madelung deformity cases displayed a Vickers ligament or radiotriquetral ligament. CONCLUSION: The radiotriquetral ligament is an anomalous ligament that is a constant and distinguishing finding in classic Madelung deformity in this study. Awareness of the radiotriquetral ligament and distinguishing it from Vickers ligament on imaging studies and at surgery may have clinical implications that need to be further investigated.

Treatment of Madelung Deformity With Vicker Ligament Release and Radial Physiolyses: A Case Series.

PURPOSE: To evaluate the surgical outcomes in a series of Madelung wrists treated with a Vicker ligament release at a young age. We hypothesize that early treatment of Madelung deformity with Vicker ligament release is safe and may minimize progression of deformity. METHODS: A retrospective review was performed at a single large pediatric institution from 2013 to 2016 of patients with a diagnosis of Madelung deformity treated with Vicker ligament release and radial physiolysis. Exclusion criteria included patients who were skeletally mature, who underwent osteotomy procedures, or who had incomplete follow-up. Patient demographics were collected, concomitant surgeries were recorded, and outcomes including range of motion and pain were documented. Measurements of standard anteroposterior and lateral radiographs were calculated before and after surgery to monitor radiographic deformity and progression. RESULTS: Six girls with bilateral Madelung deformity who underwent bilateral Vicker ligament resection and radial physiolysis (12 total wrists) were included. The average age at presentation was 7.5 years (range, 7-9 years), with an average follow-up of 30 months. Reasons for presentation included sports injuries (2), ulnar-sided wrist pain (2), and mild deformity (2). Additional radial and ulnar epiphysiodeses were performed in 2 wrists each. There were no intraoperative complications. Although pain resolved within the first month after surgery for all patients, 2 patients had intermittent unilateral ulnar-sided wrist pain at final follow-up. All patients returned to their presurgery activities. There was no loss of range of motion, and 4 wrists with preoperative supination deficits improved by an average of 17°. Radiographic measurements demonstrated improvement in the radial physeal angle in 10 out of 12 wrists (83%). No patients displayed worsening deformity after surgery. Two patients underwent subsequent procedures. CONCLUSIONS: In patients with early Madelung deformity, Vicker ligament release with radial physiolysis is a safe treatment option that theoretically has the potential to minimize the progression of radiographic deformity. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic V.

The prevalence and volumetry of pituitary cysts in children with growth hormone deficiency and idiopathic short stature.

Background Pituitary cysts have been speculated to cause endocrinopathies. We sought to describe the prevalence and volumetry of pituitary cysts in patients with growth hormone deficiency (GHD) and idiopathic short stature (ISS). Methods Six hundred and eighteen children evaluated for growth failure at the Division of Pediatric Endocrinology at New York Medical College between the years 2002 and 2012, who underwent GH stimulation testing and had a brain magnetic resonance imaging (MRI) prior to initiating GH treatment were randomly selected to be a part of this study. High resolution MRI was used to evaluate the pituitary gland for size and the presence of a cyst. Cyst prevalence, cyst volume and percentage of the gland occupied by the cyst (POGO) were documented. Results Fifty-six patients had a cyst, giving an overall prevalence of 9.1%. The prevalence of cysts in GHD patients compared to ISS patients was not significant (13.5% vs. 5.7%, p=0.46). Mean cyst volume was greater in GHD patients than ISS patients (62.0 mm3 vs. 29.4 mm3, p=0.01). POGO for GHD patients was significantly greater (p=0.003) than for ISS patients (15.3%±12.8 vs. 7.1%±8.0). Observers were blinded to patient groups. Conclusions GHD patients had a significantly greater volume and POGO compared to ISS patients. This raises the question of whether cysts are implicated in the pathology of growth failure.

Surgical Treatment of a Rare "Reverse" Madelung Deformity in 11 Years Female Patient.

Madelung deformity is an abnormality of the distal part of the forearm due to a growth arrest in the distal radial physis creating an increase of the radial tilt angle associated with a dorsal subluxation of the distal ulna in most cases. It is a rare condition which represents only 1.7% of hand deformities being characterized by the presence of an abnormal structure, Vickers ligament, that tethers the distal radius to the lunate bone. Although it is believed to be a congenital disorder, the symptoms are absent till late childhood. We present a case of a 11 years old girl patient, who came to our clinic for deformity of both forearms, which consisted of an anteriorly curved radius, volar proeminence of the distal ulna, partial limitation of supination and pain in the last 6 months, with and insidious onsed and aggravated lately. The mother of the patient, at the age of 13, was diagnosed with the same deformity which was surgically treated at that time. Furthermore, the patient has an older sister with no deformity of the forearms. X-rays revealed an increased radial tilt and anterior luxation of the distal ulna. Considering the deformity and the presence of pain we decided to excise the Vickers ligament and make an opening and derotation wedge osteotomy of the distal radius.