Endoscopic strip craniectomy with orthotic helmeting for safe improvement of head growth in children with Apert syndrome.

OBJECTIVE: Bilateral coronal craniosynostosis in Apert syndrome is traditionally managed with open cranial vault remodeling procedures like fronto-orbital advancement (FOA). However, as minimally invasive procedures gain popularity, limited data exist to determine their efficacy in this syndromic population. This study examines whether endoscopic strip craniectomy (ESC) is inferior to FOA in correcting head growth in patients with Apert syndrome. METHODS: The authors conducted a retrospective review of children with Apert syndrome over a 23-year period. Postoperative head circumferences until 24 months of age were compared for patients treated with ESC versus FOA by using normative growth curves. Intraoperative and postoperative morbidity was compared between groups. RESULTS: The median postoperative follow-up for the FOA (n = 14) and ESC (n = 16) groups was 40 and 28.5 months, the median age at operation was 12.8 and 2.7 months, and the median operative time was 285 and 65 minutes, respectively (p < 0.001). The FOA group had significantly higher rates of blood transfusion, ICU admission, and longer hospital length of stay (p < 0.01). There were no statistically significant differences in premature reossification rates, complications, need for further procedures, or complaints of asymmetry. Compared to normative growth curves, all patients in both groups had head circumferences comparable to or above the 85th percentile at last follow-up. CONCLUSIONS: Children with Apert syndrome and bilateral coronal craniosynostosis treated with ESC experience early normalization of head growth and cephalic index that is not inferior to those treated with FOA. Longer-term assessments are needed to determine long-term aesthetic results and the correlation between head growth and neurocognitive development in this population.

Pfeiffer-like syndrome with holoprosencephaly: a newborn with maternal smoking and alcohol exposure.

We report the case of a female infant with Pfeiffer-like syndrome and holoprosencephaly. She had a cloverleaf skull, ocular proptosis, broad thumbs and halluces, and variable accompanying anomalies compatible with Pfeiffer syndrome. She also displayed microcephaly, short palpebral fissures, and a smooth philtrum, which are clinical signs consistent with fetal alcohol syndrome. She suffered from multiple congenital anomalies and died at 41 days of age. Cardio-pulmonary failure, brain abnormalities, prematurity, and multiple complications contributed to her death. The patient displayed normal chromosomal numbers and type. DNA analysis did not reveal fibrobtast growth factor receptor (FGFR) genes FGFR1, FGFR2, FGFR3 or TWIST gene mutations. We review the previous reports of Pfeiffer syndrome and holoprosencephaly and describe our infant patient with Pfeiffer-like syndrome, holoprosencephaly, and heavy in utero maternal alcohol and smoking exposures.

Varón de 3 años de edad con rasgos dismórficos y craneosinostosis: síndrome de Saethre-Chotzen / A three year old boy with dysmorphic and craniosynostosis traits: Saethre-Chotzen syndrome

Se comunica el caso de un niño con el síndrome de Saethre-Chotzen (acrocefalosindactilia de tipo III), una de las craneosinostosis más frecuentes, y se describe la mutación causal en el gen TWIST (AU)

It is informed of a child with the Saethre-Chotzen syndrome (acrocephalosyndactylia of type III), one of the most frequent craniosynostosis, and it is described as a causal mutation in the TWIST gene (AU)

Análise histológica, histoquímica e imunohistoquímica da mucosa de palato duro em pacientes portadores de síndrome de Apert / Histological, histochemical and immunohistochemical analysis of the hard palate mucosa in patients with Apert syndrome

Avaliou-se a mucosa de palato duro de indivíduos portadores de síndrome de Apert, atendidos no Hospital de Reabilitação de Anomalias Craniofaciais da Universidade de São Paulo. Doze indivíduos foram submetidos à gengivectomia de tecido exuberante da mucosa palatina para colocação de bandas e acessórios ortodônticos. Os tecidos excisados foram submetidos à análise histológica, morfométrica, histoquímica (PAS, Alcian Blue e Picrossírius) e imunohistoquímica, para observação da proliferação celular com a proteína P63 e identificação de colágeno I e III e decorina. A análise histológica evidenciou epitélio hiperplásico, conjuntivo com áreas de fibras colágenas espessas de trajeto mais linear com fibrócitos em seu interior, áreas com menor número de fibras e marcante presença de fibroblastos, diferente da arquitetura do grupo controle. Os resultados da morfometria não mostraram diferença significativa entre a proporcionalidade dos componentes do tecido conjuntivo nos indivíduos com síndrome de Apert e de indivíduos do grupo controle. Os aspectos histoquímicos evidenciaram que os indivíduos com a síndrome apresentaram maior acúmulo de glicosaminoglicanas em relação ao grupo controle. A coloração de picrossírius, analisada por microscópio confocal e pelo sistema de análise de imagem Image-Pro-Plus evidenciou a presença de fibras colágenas mais espessas nos indivíduos portadores de síndrome de Apert, mas não mostrou diferença significativa entre os dois grupos. A correlação da área ocupada pelas fibras colágenas com a idade dos indivíduos não foi significativa. Os resultados da imunohistoquímica confirmaram a presença de colágeno I e III no tecido Apert, sem evidenciar a atividade proliferativa dos fibroblastos. A maioria dos cortes não evidenciou a imunomarcação para decorina. Conclui-se que o aumento de volume na mucosa palatina em indivíduos portadores de síndrome de Apert é decorrente...

The aim of this study was to evaluate the oral mucosa of patients with Apert syndrome attended at the Hospital of Rehabilitation and Craniofacial Anomalies. The gingivectomy was realized in twelve patients with gingival lateral swellings targeting orthodontic accessories. The specimens were submitted for histological, morphometric, histochemistry (PAS, Alcian Blue, picrossirius) and immunohistochemistry analysis to evaluate cell proliferation with P63 protein, and identification of the collagens I and III and decorin. The histological analysis showed a hyperplasic epithelium, areas of thick collagen fibers in the connective tissue with inactive fibroblasts, different that revealed in the control group. The proportion of the components of the connective tissue between the Aperts syndrome and the control groups wasnt statistical significant. The histochemicals features showed a high concentration of glycosaminoglycans in the connective tissue of Aperts syndrome compared with that revealed in the control group. The picrossírius stained, in the confocal microscope and in the Image Pro-Plus system showed the presence of dense collagen fibers in the Aperts syndrome group, but the statistical analysis wasnt significant between the both groups. The correlation between the collagen area and the age of the patients wasnt statistically significant. The analyses in the Apert syndrome group confirmed the presence of type -I and -III collagen and no proliferative activity of fibroblasts. The decorin staining was absent in almost all the specimens. We conclude that in Aperts syndrome gingival lateral swellings is a secondary outcome and is independent of a increase in the connective tissue components; the collagen fibers, and the glycosaminoglycans gathering found in the Apert syndrome patients were structurally different.

The study of abnormal bone development in the Apert syndrome Fgfr2+/S252W mouse using a 3D hydrogel culture model.

Apert syndrome is caused by mutations in fibroblast growth factor receptor 2 (Fgfr2) and is characterized by craniosynostosis and other skeletal abnormalities. The Apert syndrome Fgfr2+/S252W mouse model exhibits perinatal lethality. A 3D hydrogel culture model, derived from tissue engineering strategies, was used to extend the study of the effect of the Fgfr2+/S252W mutation in differentiating osteoblasts postnatally. We isolated cells from the long bones of Apert Fgfr2+/S252W mice (n=6) and cells from the wild-type sibling mice (n=6) to be used as controls. During monolayer expansion, Fgfr2+/S252W cells demonstrated increased proliferation and ALP activity, as well as altered responses of these cellular functions in the presence of FGF ligands with different binding specificity (FGF2 or FGF10). To better mimic the in vivo disease development scenario, cells were also encapsulated in 3D hydrogels and their phenotype in 3D in vitro culture was compared to that of in vivo tissue specimens. After 4 weeks in 3D culture in osteogenic medium, Fgfr2+/S252W cells expressed 2.8-fold more collagen type I and 3.3-fold more osteocalcin than did wild-type controls (p<0.01). Meanwhile, Fgfr2+/S252W cells showed decreased bone matrix remodeling and expressed 87% less Metalloprotease-13 and 71% less Noggin (p<0.01). The S252W mutation also led to significantly higher production of collagen type I and II in 3D as shown by immunofluorescence staining. In situ hybridization and alizarin red S staining of postnatal day 0 (P0) mouse limb sections demonstrated significantly higher levels of osteopontin expression and mineralization in Fgfr2+/S252W mice. Complementary to in vivo findings, this 3D hydrogel culture system provides an effective in vitro venue to study the pathogenesis of Apert syndrome caused by the analogous mutation in humans.

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 Muenke's 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 Muenke's syndrome. Contrary to previous reports, SCS patients with complete loss of one TWIST allele showed normal mental development.

Twist is required for establishment of the mouse coronal suture.

Cranial sutures are the growth centres of the skull, enabling expansion of the skull to accommodate rapid growth of the brain. Haploinsufficiency of the human TWIST gene function causes the craniosynostosis syndrome, Saethre-Chotzen syndrome (SCS), in which premature fusion of the coronal suture is a characteristic feature. Previous studies have indicated that Twist is expressed in the coronal suture during development, and therefore that it may play an important role in development and maintenance of the suture. The Twist-null mouse is lethal before the onset of osteogenesis, and the heterozygote exhibits coronal suture synostosis postnatally. In this study we investigated the function of Twist in the development of the mouse coronal suture, by inhibiting Twist synthesis using morpholino antisense oligonucleotides in calvarial organ culture. Decreased Twist production resulted in a narrow sutural space and fusion of bone domains within 48 h after the addition of the morpholino oligonucleotides. Proliferation activity in the sutural cells was decreased, and the expression of osteogenic marker genes such as Runx2 and Fgfr2 was up-regulated in the developing bone domain within 4 h. These results suggest that during establishment of the suture area, Twist is required for the regulation of sutural cell proliferation and osteoblast differentiation.

[Complex craniofacial synostoses]. / Komplekse kraniofaciale synostoser.

BACKGROUND: Complex craniofacial synostosis is a group of rare genetic disorders characterized by premature closure of the sutures in the craniofacial skeleton and which to varying degrees affects the extremities. MATERIAL AND METHODS: On the basis of relevant literature, we present a review of syndromal craniofacial synostosis. RESULTS: Phenotypically, the complex craniofacial syndromes have many similarities. Synostosis of the sutures of the cranial vault can result in a variety of skull deformations, depending on the sutures involved, the sequence of premature closure, and the time of closure. Synostosis of the sutures in the skull base and facial skeleton leads to shallow orbits, exophthalmus, hypertelorism, midface retrusion, and prognathia. INTERPRETATION: Precise diagnosis of complex craniofacial syndromes may be difficult solely on the basis of a clinical examination. However, several of the most common syndromes are caused by mutations in genes that code for fibroblast growth-factor receptors. Children with a suspected complex craniofacial syndrome should be referred to genetic testing.

Pfeiffer Syndrome type 2--case report.

OBJECTIVE: To report on a case of Pfeiffer Syndrome, with a discussion of the diagnostic characteristics and features of disease types and the differential diagnosis. DESCRIPTION: The authors describe a newborn with cloverleaf skull, extreme bilateral exorbitism and choanal atresia, partial syndactyly of the second and third toes and broad medially-deviated big toes. The case reported was Pfeiffer Syndrome type 2, which usually has a poor prognosis. COMMENTS: Pfeiffer Syndrome is a clinically variable disorder and consists of an autosomal dominantly-inherited osteochondrodysplasia with craniosynostosis. It has been divided into three types. Type 1 is commonly associated with normal intelligence and generally good outcome. Types 2 and 3 generally have severe neurological compromise, poor prognosis, early death and sporadic occurrence. Potential for prolonged useful survival outcome can be achieved in some cases with early aggressive medical and surgical management according to recent literature.

Toward pathogenesis of Apert cleft palate: FGF, FGFR, and TGF beta genes are differentially expressed in sequential stages of human palatal shelf fusion.

OBJECTIVE: Critical cellular events at the palatal medial edge epithelium (MEE) occur in unperturbed mammalian palatogenesis, the molecular control of which involves a number of growth factors including transforming growth factor beta 3 (TGF beta 3). Apert syndrome is a monogenic human disorder in which cleft palate has been significantly correlated to the fibroblast growth factor receptor (FGFR) 2-Ser252Trp mutation. We report the relative expression of these genes in human palatogenesis. METHODS: The expression of the IgIIIa/b and IgIIIa/c transcript isoforms of FGFR2 and the proteins FGFR1, FGFR2, and FGFR3 was studied in situ throughout the temporospatial sequence of human palatal shelf fusion and correlated with the expression of TGF beta 3. In addition, the immunolocalization of the ligand FGFs 2, 4, and 7 was undertaken together with the intracellular transcription factor STAT1, which is activated by FGFR signaling. RESULTS: FGFRs are differentially expressed in the mesenchyme and epithelia of fusing palatal shelves, in domains overlapping those of their ligands FGF4 and FGF2 but not FGF7. Coexpression is seen with TGF beta 3, which is implicated in MEE dynamics and FGF and FGFR upregulation, and STAT1, an intracellular transcription factor that mediates apoptosis. CONCLUSIONS: The coregulation of molecules of the FGFR signaling pathway with TGF beta 3 throughout the stages of human palatal fusion suggests their controlling influence on apoptosis and epitheliomesenchymal transdifferentiation at the MEE. Experimental evidence links FGFR2-IgIIIa/b loss of function with palatal clefting, and these correlated data suggest a unique pathological mechanism for Apert cleft palate.

Echoencephalographic findings of Apert syndrome.

Although Apert syndrome has been characterized in the prenatal period and clinically described in the literature, postnatal echoencephalographic findings have not been reported. We present a case of Apert syndrome that shows bilateral periventricular cysts, unusual posterior downward curving of the lateral ventricles without evidence of hydrocephalus, along with a decreased anterior-posterior diameter of the cranial vault. Given that Apert syndrome, characterized by acrocephalosyndactyly, can give rise to numerous CNS abnormalities, echoencephalography could be used to further characterize Apert syndrome in the postnatal period.

Pfeiffer syndrome caused by haploinsufficient mutation of FGFR2.

Mutations of the fibroblast growth factor receptors (FGFRs) cause several dominantly inherited congenital skeletal disorders and syndromes. Recently, these mutations have been suggested to cause either ligand-independent activation of the receptor or a dominant negative inactivation. The analysis of two Japanese patients with Pfeiffer syndrome and postaxial polydactyly of the hand now shows that both carried the same 1119-2A-to-G transition of the FGFR2 gene and this nonsense mutation caused skipping of exon 9(B) and haploinsufficiency of FGFR2.

Molecular basis of congenital hypopigmentary disorders in humans: a review.

Many specific gene products are sequentially made and utilized by the melanocyte as it emigrates from its embryonic origin, migrates into specific target sites, synthesizes melanin(s) within a specialized organelle, transfers pigment granules to neighboring cells, and responds to various exogenous cues. A mutation in many of the respective encoding genes can disrupt this process of melanogenesis and can result in hypopigmentary disorders. Following are examples highlighting this scenario. A subset of neural crest derived cells emigrate from the dorsal surface of the neural tube, become committed to the melanoblast lineage, and are targeted along the dorsal lateral pathway. The specific transcription factors PAX3 and MITF (microphthalmia transcription factor) appear to play a regulatory role in early embryonic development of the pigment system and in associated diseases (the Waardenburg syndromes). During the subsequent development and commitment of the melanoblast, concomitant expression of the receptors for fibroblasts growth factor (FGFR2), endothelin-B (EDNRB), and steel factor (cKIT) also appears essential for the continued survival of migrating melanoblasts. Lack or dysfunction of these receptors result in Apert syndrome, Hirschsprung syndrome and piebaldism, respectively. Once the melanocyte resides in its target tissue, a plethora of melanocyte specific enzymes and structural proteins are coordinately expressed to form the melanosome and to convert tyrosine to melanin within it. Mutations in the genes encoding these proteins results in a family of congenital hypopigmentary diseases called oculocutaneous albinism (OCA). The tyrosinase gene family of proteins (tyrosinase, TRP1, and TRP2) regulate the type of eumelanin synthesized and mutations affecting them result in OCA1, OCA3, and slaty (in the murine system), respectively. The P protein, with 12 transmembrane domains localized to the melanosome, has no assigned function as of yet but is responsible for OCA2 when dysfunctional. There are other genetically based syndromes, phenotypically resembling albinism, in which the synthesis of pigmented melanosomes, as well as specialized organelles of other cell types, is compromised. The Hermansky-Pudlak syndrome (HPS) and the Chediak-Higashi syndrome (CHS) are two such disorders. Eventually, the functional melanocyte must be maintained in the tissue throughout life. In some cases it is lost either normally or prematurely. White hair results in the absence of melanocytes repopulating the germinative hair follicle during subsequent anagen stages. Vitiligo, in contrast, results from the destruction and removal of the melanocyte in the epidermis and mucous membranes.

Pregnancies and offspring in survivors of acute lymphoid leukemia and lymphoma.

Since few data on the reproductive outlook of patients successfully treated for lymphoproliferative disease are available, further experiences on the pregnancy outcome and offspring follow-up of 12 women treated for acute lymphoid leukemia and 7 women treated for malignant lymphoma are reported. Of the 20 pregnancies of leukemic patients in remission, 14 ended in live births, one in spontaneous abortion, and 5 in elective abortions among which one was performed during relapse. One minor (hip dysplasia) and one major birth defect (Apert syndrome) were seen. The Apert syndrome baby is considered as a new mutation. Of the 9 pregnancies of lymphoma patients 5 ended in normal births and 4 in elective abortions. Neither relapse nor malformation was encountered. One leukemic patient had gestational edema and one lymphoma patient had puerperal thrombophlebitis of lower extremity. The offspring of the above patients appropriately developed and had no complication except for one with cephalhematoma and for another one with epilepsy attributed to birth injury.