Hartmut Collmann

Hydrocephalus in craniosynostosis: a review

IntroductionVentricular dilatation in the presence of primary craniosynostosis is a unique condition with respect to pathogenesis, clinical significance, and morphological appearance. It is rarely observed in nonsyndromic craniosynostosis, and in these cases usually attributable to coincidental disorders. Conversely, it is a common feature of syndromic craniosynostosis, affecting at least 40% of patients with Crouzon’s, Pfeiffer’s or the Apert syndrome. Shunt-dependent hydrocephalus is predominantly associated with Crouzon or Pfeiffer syndrome while in the Apert syndrome the usual finding is nonprogressive ventriculomegaly which, however, may also occur in some cases of Crouzon syndrome.PathogenesisThe pathogenesis of progressive hydrocephalus remains somewhat obscure, a hypoplastic posterior fossa and a venous outlet occlusion at the skull base being the main causative factors discussed in literature. Ventriculomegaly may reflect primary brain maldevelopment or in some cases even a compensated state of increased cerebrospinal fluid (CSF) outflow resistance.Clinical evaluation Clinical evaluation is mainly aimed at identifying progressive hydrocephalus, but diagnosis is hampered by the fact that classical clinical signs may be absent, and that ventricular dilatation will often become evident only after decompressive cranial surgery. Moreover, mild ventriculomegaly may in some cases coexist with intracranial hypertension from craniostenosis. Therefore, careful monitoring of intracranial pressure and ventricular size in the pre- and postoperative period is a diagnostic mainstay.Conclusion In true hydrocephalus ventriculo-peritoneal shunting is currently the single promising mode of treatment.

Saethre–Chotzen syndrome caused by TWIST 1 gene mutations: functional differentiation from Muenke coronal synostosis syndrome

The Saethre–Chotzen syndrome (SCS) is an autosomal dominant craniosynostosis syndrome with uni- or bilateral coronal synostosis and mild limb deformities. It is caused by loss-of-function mutations of the TWIST 1 gene. In an attempt to delineate functional features separating SCS from Muenkes syndrome, we screened patients presenting with coronal suture synostosis for mutations in the TWIST 1 gene, and for the Pro250Arg mutation in FGFR3. Within a total of 124 independent pedigrees, 39 (71 patients) were identified to carry 25 different mutations of TWIST 1 including 14 novel mutations, to which six whole gene deletions were added. The 71 patients were compared with 42 subjects from 24 pedigrees carrying the Pro250Arg mutation in FGFR3 and 65 subjects from 61 pedigrees without a detectable mutation. Classical SCS associated with a TWIST 1 mutation could be separated phenotypically from the Muenke phenotype on the basis of the following features: low-set frontal hairline, gross ptosis of eyelids, subnormal ear length, dilated parietal foramina, interdigital webbing, and hallux valgus or broad great toe with bifid distal phalanx. Functional differences were even more important: intracranial hypertension as a consequence of early progressive multisutural fusion was a significant problem in SCS only, while mental delay and sensorineural hearing loss were associated with the Muenkes syndrome. Contrary to previous reports, SCS patients with complete loss of one TWIST allele showed normal mental development.

Cutaneous lesions in occult spinal dysraphism—correlation with intraspinal findings

ObjectsThis study was conducted to investigate the frequency and type of cutaneous stigmata in different forms of occult spinal dysraphism (OSD) and their correlation to the underlying malformation.MethodsFourteen different forms of spinal malformations were identified in 358 operated patients with OSD. Most frequent findings (isolated or in combinations) were spinal lipoma, split cord malformation, pathologic filum terminale, dermal sinus, meningocele manqué, myelocystocele and caudal regression. Stigmata were present in 86.3% of patients, often in various combinations. Using a binary logistic regression analysis, significant correlations with distinct malformations were found for subcutaneous lipomas, skin tags, vascular nevi, pori, hairy patches, hypertrichosis, meningoceles and “cigarette burn” marks.ConclusionsCutaneous markers in a high percentage accompany spinal malformations. Due to the correlations of different stigmata to distinct malformations, they can aid the clinician in further diagnostic and therapeutic work.

An unusual FGFR1 mutation (fibroblast growth factor receptor 1 mutation) in a girl with non-syndromic trigonocephaly.

Non-syndromic trigonocephaly is a heterogeneous entity; in most cases the origin is unknown. Rare cases with autosomal dominant and recessive inheritance exist. Here the mutational screening of ten patients in the FGFR1, 2, and 3 genes and the TWIST gene causative of autosomal dominant craniosynostosis syndromes was reported. In one girl an unusual FGFR1 mutation was found.

Neurosurgical aspects of childhood hypophosphatasia

ObjectiveHypophosphatasia (HPP; MIM241510) is a rare inborn error of bone metabolism of recessive inheritance. It is caused by mutations in the gene encoding the tissue-nonspecific alkaline phosphatase. Apart from problems in bone mineralization, growth failure, and premature loss of decidual teeth, the infantile and the childhood types of HPP are associated with premature fusion of cranial sutures.PatientsWe report on seven children affected with infantile and childhood HPP who presented with craniosynostosis.ResultsNeurosurgical intervention was necessary in four of them because of intracranial hypertension. In one of these, severe dural calcification posed an unexpected problem during surgery. Secondary ectopia of the cerebellar tonsils were detected in five of the seven patients and caused hydrosyringomyelia in one of them.ConclusionsSince cranial sutures are frequently involved in infantile and childhood HPP, a multidisciplinary approach for the clinical care is necessary, including long-term neurosurgical surveillance.

Avoiding CT scans in children with single-suture craniosynostosis

IntroductionDuring the last decades, computed tomography (CT) has become the predominant imaging technique in the diagnosis of craniosynostosis. In most craniofacial centers, at least one three-dimensional (3D) computed tomographic scan is obtained in every case of suspected craniosynostosis. However, with regard to the risk of radiation exposure particularly in young infants, CT scanning and even plain radiography should be indicated extremely carefully.Material and methodsOur current diagnostic protocol in the management of single-suture craniosynostosis is mainly based on careful clinical examination with regard to severity and degree of the abnormality and on ophthalmoscopic surveillance. Imaging techniques consist of ultrasound examination in young infants while routine plain radiographs are usually postponed to the date of surgery or the end of the first year. CT and magnetic resonance imaging (MRI) are confined to special diagnostic problems rarely encountered in isolated craniosynostosis. The results of this approach were evaluated retrospectively in 137 infants who were referred to our outpatient clinic for evaluation and/or treatment of suspected single suture craniosynostosis or positional deformity during a 2-year period (2008–2009).ResultsIn 133 (97.1%) of the 137 infants, the diagnosis of single-suture craniosynostosis (n = 110) or positional plagiocephaly (n = 27) was achieved through clinical analysis only. Two further cases were classified by ultrasound, while the remaining two cases needed additional digital radiographs. In no case was CT scanning retrospectively considered necessary for establishing the diagnosis. Yet in 17.6% of cases, a cranial CT scan had already been performed elsewhere (n = 16) or had been definitely scheduled (n = 8).ConclusionCT scanning is rarely necessary for evaluation of single-suture craniosynostosis. Taking into account that there is a quantifiable risk of developing cancer in further lifetime, every single CT scan should be carefully indicated.

Effective NSAID treatment indicates that hyperprostaglandinism is affecting the clinical severity of childhood hypophosphatasia.

BackgroundHypophosphatasia (HP) is an inborn error of bone metabolism characterized by a genetic defect in the gene encoding the tissue-nonspecific alkaline phosphatase (TNSALP). There is a lack of knowledge as to how the variability and clinical severity of the HP phenotype (especially pain and walking impairment) are related to metabolic disturbances or impairments, subsequent to the molecular defect.MethodsWe analyzed the changes in clinical symptoms and the prostaglandin (PG) metabolism in response to treatment with non-steroidal anti-inflammatory drugs (NSAIDs) in six children affected by childhood HP. In addition, by exposing HP fibroblasts to pyridoxal phosphate and/or calcium pyrophosphate in vitro, we analyzed whether the alterations in PG levels are sequelae related to the metabolic defect.ResultsChildhood HP patients, who often complain about pain in the lower limbs without evident fractures, have systemic hyperprostaglandinism. Symptomatic anti-inflammatory treatment with NSAIDs significantly improved pain-associated physical impairment. Calcium pyrophosphate, but not pyridoxal phosphate, induced cyclooxygenase-2 (COX-2) gene expression and PG production in HP and normal fibroblasts in vitro.ConclusionClinical features of childhood HP related to pain in the lower legs may be, at least in part, sequelae related to elevated PG levels, secondary to the primary metabolic defect. Consequently, NSAID treatment does improve the clinical features of childhood HP.

Hydrocephalus in craniosynostosis

Routine CT scanning in 221 patients with craniosynostosis revealed ventricular dilation in 40. In 5 hydrocephalus was obviously unrelated to the craniostenosis. The remaining 35 cases were associated almost exclusively with syndromic craniosynostosis. Ventricular dilation was mild in 22, moderate in 9, and marked in 4 patients. Clinical and radiological findings strongly suggest that three different mechanisms are involved in the pathogenesis of hydrocephalus: primary cerebral maldevelopment, brain atrophy, and CSF outflow obstruction. In the diagnosis of hydrostatic hydrocephalus with craniosynostosis, head circumference is no indicator of progressive hydrocephalus, and intracranial hypertension may be due either to CSF accumulation or to craniostenosis. The present study indicates that shunt treatment prior to correction of synostosis should be restricted to a few cases of rapidly progressing hydrocephalus. Secondary shunting of hydrocephalus may be considered if intracranial pressure remains high despite adequate cranial decompression. Shunting is not an appropriate treatment for craniostenosis — even in cases of concurrent ventricular dilation.

Mutations in the interleukin receptor IL11RA cause autosomal recessive Crouzon-like craniosynostosis

We have characterized a novel autosomal recessive Crouzon‐like craniosynostosis syndrome in a 12‐affected member family from Antakya, Turkey, the presenting features of which include: multiple suture synostosis, midface hypoplasia, variable degree of exophthalmos, relative prognathism, a beaked nose, and conductive hearing loss. Homozygosity mapping followed by targeted next‐generation sequencing identified a c.479+6T>G mutation in the interleukin 11 receptor alpha gene (IL11RA) on chromosome 9p21. This donor splice‐site mutation leads to a high percentage of aberrant IL11RA mRNA transcripts in an affected individual and altered mRNA splicing determined by in vitro exon trapping. An extended IL11RA mutation screen was performed in a cohort of 79 patients with an initial clinical diagnosis of Crouzon syndrome, pansynostosis, or unclassified syndromic craniosynostosis. We identified mutations segregating with the disease in five families: a German patient of Turkish origin and a Turkish family with three affected sibs all of whom were homozygous for the previously identified IL11RA c.479+6T>G mutation; a family with pansynostosis with compound heterozygous missense mutations, p.Pro200Thr and p.Arg237Pro; and two further Turkish families with Crouzon‐like syndrome carrying the homozygous nonsense mutations p.Tyr232* and p.Arg292*. Using transient coexpression in HEK293T and COS7 cells, we demonstrated dramatically reduced IL11‐mediated STAT3 phosphorylation for all mutations. Immunofluorescence analysis of mouse Il11ra demonstrated specific protein expression in cranial mesenchyme which was localized around the coronal suture tips and in the lambdoidal suture. In situ hybridization analysis of adult zebrafish also detected zfil11ra expression in the coronal suture between the overlapping frontal and parietal plates. This study demonstrates that mutations in the IL11RA gene cause an autosomal recessive Crouzon‐like craniosynostosis.

Muenke syndrome: An international multicenter natural history study

Muenke syndrome is an autosomal dominant disorder characterized by coronal suture craniosynostosis, hearing loss, developmental delay, carpal, and calcaneal fusions, and behavioral differences. Reduced penetrance and variable expressivity contribute to the wide spectrum of clinical findings. Muenke syndrome constitutes the most common syndromic form of craniosynostosis, with an incidence of 1 in 30,000 births and is defined by the presence of the p.Pro250Arg mutation in FGFR3. Participants were recruited from international craniofacial surgery and genetic clinics. Affected individuals, parents, and their siblings, if available, were enrolled in the study if they had a p.Pro250Arg mutation in FGFR3. One hundred and six patients from 71 families participated in this study. In 51 informative probands, 33 cases (64.7%) were inherited. Eighty‐five percent of the participants had craniosynostosis (16 of 103 did not have craniosynostosis), with 47.5% having bilateral and 28.2% with unilateral synostosis. Females and males were similarly affected with bicoronal craniosynostosis, 50% versus 44.4% (P = 0.84), respectively. Clefting was rare (1.1%). Hearing loss was identified in 70.8%, developmental delay in 66.3%, intellectual disability in 35.6%, attention deficit/hyperactivity disorder in 23.7%, and seizures in 20.2%. In patients with complete skeletal surveys (upper and lower extremity x‐rays), 75% of individuals were found to have at least a single abnormal radiographical finding in addition to skull findings. This is the largest study of the natural history of Muenke syndrome, adding valuable clinical information to the care of these individuals including behavioral and cognitive impairment data, vision changes, and hearing loss.