Distinctive Craniofacial Features Research Articles

Mutations in SCARF2 Are Responsible for Van Den Ende-Gupta Syndrome

Van Den Ende-Gupta syndrome (VDEGS) is an extremely rare autosomal-recessive disorder characterized by distinctive craniofacial features, which include blepharophimosis, malar and/or maxillary hypoplasia, a narrow and beaked nose, and an everted lower lip. Other features are arachnodactyly, camptodactyly, peculiar skeletal abnormalities, and normal development and intelligence. We present molecular data on four VDEGS patients from three consanguineous Qatari families belonging to the same highly inbred Bedouin tribe. The patients were genotyped with SNP microarrays, and a 2.4 Mb homozygous region was found on chromosome 22q11 in an area overlapping the DiGeorge critical region. This region contained 44 genes, including SCARF2, a gene that is expressed during development in a number of mouse tissues relevant to the symptoms described above. Sanger sequencing identified a missense change, c.773G>A (p.C258Y), in exon 4 in the two closely related patients and a 2 bp deletion in exon 8, c.1328_1329delTG (p.V443DfsX83), in two unrelated individuals. In parallel with the candidate gene approach, complete exome sequencing was used to confirm that SCARF2 was the gene responsible for VDEGS. SCARF2 contains putative epidermal growth factor-like domains in its extracellular domain, along with a number of positively charged residues in its intracellular domain, indicating that it may be involved in intracellular signaling. However, the function of SCARF2 has not been characterized, and this study reports that phenotypic effects can be associated with defects in the scavenger receptor F family of genes.

P49 A 33-year-old woman with nevoid basal cell carcinoma syndrome presenting with multiple nodular, nodulocystic, ulcerating and superficial basal cell carcinomas predominantly localized in the head and neck region. Case report and review of therapeutic options

Case report A 33-year-old woman was referred to our centre for therapeutic advice concerning multiple slow-growing skin lesions on the scalp and face. In 2003, the clinical diagnosis of nevoid basal cell carcinoma (NBCCS) was made based on a history of odontogenic keratocysts, distinct craniofacial features (frontal bossing, hypertelorism and coarse face), calcification of the falx cerebri and dura mater, segmentation defect of cervical vertebrae C5-C6, seizures, cardiac fibroma and mesenteric cysts. Genetic testing with DHPLC technique on leucocytes confirmed a germline mutation in patched 1 (PTCH1) gene on chromosome 9q22.3 in 2007. The first dermatological examination in 2009 revealed multiple lesions in the head and neck region, most of them clinically suspect for nodular or nodulo-ulcerative basal cell carcinomas (BCCs). Lesions suspect for superficial BCCs were predominantly observed on the lower limbs and to a lesser extent in the head and neck region. Patient presented also with dermal naevi, in the face and neck region, which could be differentiated from small nodular BCCs through dermoscopy. We did not observe palmoplantar pits, milia or epidermal cysts. The BCCs, which clinically presented as nodular or nodulo-ulcerative lesions, were treated with surgical excision to ensure optimal cure rate. In total 19 lesions were removed. Histological review showed 17 nodular BCCs and 2 BCCs of the superficial type. Non-surgical treatments, such as topical 5-fluorouracil and topical 5% imiquimod or photodynamic therapy which offer better cosmetic outcome, are treatment options for superficial BCCs. The therapeutic challenge in this genetically impaired patient lies in the expected development of a large number of BCCs with repeated occurrence throughout life. Radiotherapy should be avoided in the treatment of BCC in NBCCS since ionizing radiation may lead to the development of new BCCs in the field of irradiation. In this patient, for whom oral contraception is prohibited due to a history of thrombophilia, oral retinoids are relatively contra-indicated due to their teratogenic effects. In this regard, hedgehog/smoothened inhibitor molecules may provide a long-term option in the treatment of early lesions, in order to avoid surgery with its possible functional defects and unaesthetic consequences. These molecules bind with high affinity to Smoothened protein and substitute for the lost protein PTCH1 function by inhibiting Hedgehog pathway activation. Since available oral molecules are reserved for locally advanced or metastatic BCCs, we opted for inclusion in a clinical trial concerning a topical specific Smoothened inhibitor.

Partial 7q11.23 deletions further implicate GTF2I and GTF2IRD1 as the main genes responsible for the Williams–Beuren syndrome neurocognitive profile

BackgroundWilliams–Beuren syndrome (WBS) is a developmental disorder with multisystemic manifestations mainly characterised by vascular stenoses, distinctive craniofacial features, mental retardation with a characteristic neurocognitive profile, and some endocrine and connective...

A newborn with Cornelia de Lange syndrome: a case report

Cornelia de Lange syndrome (CdLS) is a rarely seen multisystem developmental disorder syndrome characterized by facial dysmorphia (arched eyebrows, synophrys, depressed nasal bridge, long philtrum, down-turned angles of the mouth), upper-extremity malformations, hirsutism, cardiac defects, growth and cognitive retardation, and gastrointestinal abnormalities. The features of this disorder vary widely among affected individuals and range from relatively mild to severe. Early in life, the distinctive craniofacial features in mild de Lange syndrome may be indistinguishable from the severe (classical) phenotype. We present here a case of newborn with CdLs.

Homozygous deletions of a copy number change detected by array CGH: A new cause for mental retardation?

We describe two unrelated patients with mental retardation and normal karyotypes found to have relatively large homozygous deletions (>150 kb) of different regions detected by array comparative genomic hybridization (aCGH). Patient 1 showed a 157-214 kb deletion at 8q24.2, containing BAC clone RP11-17M8. This patient was born to phenotypically normal parents and has microcephaly, distinctive craniofacial features, brachymetacarpia, brachymetatarsia and severe mental retardation. This BAC clone is listed as a copy number variant on the Database of Genomic Variants (http://projects.tcag.ca/variation/). Heterozygosity for the deletion was found in the mother (father is deceased) and uniparental disomy of chromosome 8 was excluded. Patient 2 showed a 812-902 kb deletion at 12q21.1, containing BAC clone RP11-89P15. This region was not listed in any public database as a known variant. This patient has mild craniofacial dysmorphic features, bifid uvula, peripheral pulmonic stenosis and developmental delay. Heterozygosity for this deletion was confirmed in the phenotypically normal parents and two normal siblings, but surprisingly, homozygosity for the deletion in an apparently normal younger sibling brings into question whether this large homozygous copy number change (CNC) is causal. Homozygous deletions of CNCs have not previously been reported in association with a phenotype or mental retardation. These cases represent homozygosity for presumably benign CNCs, and while causality for the phenotypes cannot be confirmed, similar deletions are bound to be identified more frequently as aCGH is used with increasing regularity. Such homozygous deletions should be viewed as potentially clinically relevant.

Complex constitutional subtelomeric 1p36.3 deletion/duplication in a mentally retarded child with neonatal neuroblastoma

Monosomy 1p36 is one of the most frequent subtelomeric microdeletion syndromes characterized by distinct craniofacial features and developmental delay/mental retardation. Other common symptoms include hypotonia, seizures, brain abnormalities, visual, auditory and heart defects. Neuroblastoma is a rare feature since to our knowledge only two patients with “pure” 1p36 deletion have been described. We report on a child with developmental delay and facial dysmorphy who developed neuroblastoma at 1 month of age. No primary site outside of the liver could be demonstrated and the tumour regressed spontaneously. Standard karyotyping was normal while subtelomeric screening using Multiplex Ligation-dependent Probe Amplification (MLPA) method revealed a constitutional de novo subtelomeric 1p36 deletion. Subsequent Agilent 244K oligonucleotide array-based comparative genomic hybridization (CGH) and fluorescence in situ hybridization (FISH) analysis showed a complex 1p36.3 deletion/duplication rearrangement. Among the best candidate genes predisposing to the development of neuroblastoma located in 1p36, the AJAP1 gene is the only gene present in the duplication while CHD5, TNFRSF25 and CAMTA1 are located outside of the rearrangement. Therefore, a gene-dosage effect involving a gene located in the duplication including AJAP1 might explain the neuroblastoma observed in our patient. The rearrangement might equally interfere with the expression of a gene located outside of it (including CHD5 located 1 Mb away from the rearrangement) playing a role in the tumorigenesis. In conclusion, this study illustrates the complexity of such rearrangement characterized by array CGH and strengthens that constitutional 1p36.3 rearrangement predisposes to the development of neuroblastoma.

Treatment of macroglossia in a child with Weaver syndrome

Weaver syndrome is a rare disorder, characterized by accelerated growth, advanced osseous maturation and distinct craniofacial features. Macroglossia and hypothyroidism are seldom mentioned in the literature as clinical findings associated with the syndrome. This paper describes a patient with Weaver syndrome, referred for consultation and treatment of macroglossia, who also suffered from congenital hypothyroidism. This is the first reported case of Weaver syndrome treated with partial glossectomy (tongue reduction). The paper describes the clinical findings of the syndrome, emphasizing the difficulty in identifying it, the indications for partial glossectomy and the authors’ recommended operative technique.

Dental findings in Kabuki make‐up syndrome: a case report

This article documents the case history of a 9-year-old Brazilian child diagnosed with Kabuki make-up syndrome (KMS). The clinical features are described, with emphasis on the craniofacial and orodental manifestations. The patient had the distinctive KMS craniofacial features consisting of long palpebral fissure, hypertelorism, high-arched eyebrows with sparse hair in the lateral one-third, eyes with eversion of the lateral one-third of the lower eyelids, long and curved eyelashes, palpebral ptosis, large anteverted prominent ears in a lower position, broad, depressed nasal root with a flat nasal tip, and mild neuropsychomotor developmental deficits. The intraoral examination revealed an anterior open bite, overretention of primary teeth, and a high-arched palate. Two findings in this child have not been previously reported in patients with KMS: the presence of supernumerary teeth and taurodontic teeth in the maxillary arch. The clinical and radiographic detection of these unique dental features may be helpful in identifying children who may have milder forms of KMS.

Germline mutations of MEK in cardio-facio-cutaneous syndrome are sensitive to MEK and RAF inhibition: implications for therapeutic options

Cardio-facio-cutaneous (CFC) syndrome is a sporadic developmental disorder characterized by distinctive craniofacial features, heart defects, mental retardation and ectodermal abnormalities. We recently reported missense germline mutations in the genes MEK1 and MEK2 in patients with CFC. These mutations, including F53S and Y130C MEK1, and F57C MEK2, are the first naturally occurring mutations to be identified in these genes. This study reports data concerning the biochemical functions of the novel mutants, as well as the roles of these MEK genes in the MAPK signaling cascade. Our CFC MEK variants cannot induce ERK unless they are phosphorylated by RAF at two key serine residues in the regulatory loop. When we replaced the serine residues with alanines, ERK phosphorylation was significantly reduced in the presence of RAF. We did find that F57C MEK2 activation was less dependent on RAF signaling than the other mutants. This difference results in F57C MEK2 being resistant to the selective RAF inhibitor SB-590885. All three mutants are sensitive to the MEK inhibitor U0126. The majority of CFC cases result from mutations in B-RAF. A recent report indicates the possibility that cancer cells with activated B-RAF have enhanced, selective sensitivity to MEK inhibitors. Thus, regardless of mutations identified in an individual with CFC, MEK inhibition is a potential therapeutic approach for this population.

Leukocyte cDNA Analysis of NSD1 Derived from Confirmed Sotos Syndrome Patients

Haploinsufficiency of the NSD1 gene leads to Sotos syndrome (Sos), which is characterised by excessive growth, especially during childhood, distinct craniofacial features and variable degree of mental impairment. A wide spectrum of NSD1 mutations have been described in Sos patients, ranging from more than 100 different single nucleotide changes, to partial gene deletions, and to microdeletions of various sizes comprising the entire NSD1 locus. To investigate the NSD1 cDNA sequence in genetically confirmed Sos patients harbouring truncating and missense mutations. Total RNA was isolated from a 250 mul standard EDTA blood sample from nine genetically verified Sos patients, and subsequent reverse-transcribed into cDNA followed by PCR and direct sequencing of specific NSD1 cDNA sequences. All nine mutations, including missense, nonsense and whole exon deletions, previously identified in genomic DNA, could confidently be detected in cDNA. Several NSD1 transcript splice variants were detected. Despite the fact that Sos is caused by haploinsufficiency, NSD1 transcripts containing nonsense and frame shift mutations can be detected in leukocyte-derived cDNA. The possibility therefore exists that certain NSD1 mutations are expressed and contribute to the phenotypic variability of Sos. NSD1 cDNA analysis is likely to enhance mutation detection in Sos patients.

Polyhydramnios, megalencephaly and symptomatic epilepsy caused by a homozygous 7-kilobase deletion in LYK5

We used single nucleotide polymorphism (SNP) microarrays to investigate the cause of a symptomatic epilepsy syndrome in a group of seven distantly related Old Order Mennonite children. Autozygosity mapping was inconclusive, but closer inspection of the data followed by formal SNP copy number analyses showed that all affected patients had homozygous deletions of a single SNP (rs721575) and their parents were hemizygous for this marker. The deleted SNP marked a larger deletion encompassing exons 9-13 of LYK5, which encodes STE20-related adaptor protein, a pseudokinase necessary for proper localization and function of serine/threonine kinase 11 (a.k.a. LKB1). Homozygous LYK5 deletions were associated with polyhydramnios, preterm labour and distinctive craniofacial features. Affected children had large heads, infantile-onset intractable multifocal seizures and severe psychomotor retardation. We designated this condition PMSE syndrome (polyhydramnios, megalencephaly and symptomatic epilepsy). Thirty-eight percent (N = 16) of affected children died during childhood (ages 7 months to 6 years) from medical complications of the disorder, which included status epilepticus, congestive heart failure due to atrial septal defect and hypernatremic dehydration due to diabetes insipidus. A single post-mortem neuropathological study revealed megalencephaly, ventriculomegaly, cytomegaly and extensive vacuolization and astrocytosis of white matter. There was abundant anti-phospho-ribosomal S6 labelling of large cells within the frontal cortex, basal ganglia, hippocampus and spinal cord, consistent with constitutive activation of the mammalian target of rapamycin (mTOR) signalling pathway in brain.

RAI1 point mutations, CAG repeat variation, and SNP analysis in non‐deletion Smith–Magenis syndrome

Smith-Magenis syndrome (SMS) is a multiple congenital anomalies/mental retardation disorder characterized by distinct craniofacial features and neurobehavioral abnormalities usually associated with an interstitial deletion in 17p11.2. Heterozygous point mutations in the retinoic acid induced 1 gene (RAI1) have been reported in nine SMS patients without a deletion detectable by fluorescent in situ hybridization (FISH), implicating RAI1 haploinsufficiency as the cause of the major clinical features in SMS. All of the reported point mutations are unique and de novo. RAI1 contains a polymorphic CAG repeat and encodes a plant homeo domain (PHD) zinc finger-containing transcriptional regulator. We report a novel RAI1 frameshift mutation, c.3103delC, in a non-deletion patient with many SMS features. The deletion of a single cytosine occurs in a heptameric C-tract (CCCCCCC), the longest mononucleotide repeat in the RAI1 coding region. Interestingly, we had previously reported a frameshift mutation, c.3103insC, in the same mononucleotide repeat. Furthermore, all five single base frameshift mutations preferentially occurred in polyC but not polyG tracts. We also investigated the distribution of the polymorphic CAG repeats in both the normal population and the SMS patients as one potential molecular mechanism for variability of clinical expression. In this limited data set, there was no significant association between the length of CAG repeats and the SMS phenotype. However, we identified a 5-year-old girl with an apparent SMS phenotype who was a compound heterozygote for an RAI1 missense mutation inherited from her father and a polyglutamine repeat of 18 copies, representing the largest known CAG repeat in this gene, inherited from her mother.

Analysis of the NSD1 promoter region in patients with a Sotos syndrome phenotype

Sotos syndrome (SoS, OMIM#117550) is an overgrowth disorder characterized by excessive growth-especially in the first years of childhood-distinctive craniofacial features, and various degrees of mental retardation. Haploinsufficiency of the nuclear receptor binding SET domain containing protein 1 (NSD1) gene, due to either intragenic mutations or whole-gene microdeletions, is found in the majority of patients with SoS. However, in approximately 10-40% of patients with a typical SoS phenotype, no abnormalities are detected. In this study, hemizygous hypermethylation or genomic sequence abnormalities of the promoter region of NSD1 were hypothesized to be the underlying cause in patients with a SoS phenotype, but without confirmed NSD1 alterations. In 18 patients, including one patient with a reported hepatocellular carcinoma, the promoter region of NSD1 was analyzed. However, no hypermethylation or sequence abnormalities in the promoter region could be detected. It therefore seems unlikely that such abnormalities of NSD1 are a major culprit in patients with phenotypical SoS. Additional methods are necessary for detection of other genetic or epigenetic causes of SoS.

The relationship of distinct craniofacial features between Turner syndrome females and their parents

The present study aimed to assess the relationship of craniofacial features between females with Turner syndrome (TS) and their parents. Lateral cephalograms of 63 TS females and 80 family members with normal karyotype were analysed using 13 linear and eight angular cephalometric measurements. The statistical differences of the measurements between adult TS females and their mothers (n = 41) and between adult TS females and their adult sisters (n = 27) were calculated to define the distinct craniofacial features of subjects with TS. Regression models were computed to assess the association of distinct craniofacial features between TS females and their parents (n = 41 for mothers and n = 12 for fathers). Distinct craniofacial features of the subjects with TS were an increased cranial base flexion, shortened posterior cranial base length (S-Ba), retrognathic maxilla and mandible (<SNB), shortened distance of the palate, glenoid fossa (S-Art) and gonion (S-Go) from sella, shortened body and total length (Art-Pog) of the mandible and increased vertical angles of the facial skeleton. The mothers' S-Ba (P = 0.001), <SNB (P < 0.001), S-Go (P < 0.01) and S-Art (P < 0.05) measurements predicted well the corresponding measurements of their daughters with TS. Fathers had a significant association with their TS daughters in Art-Pog (P < 0.01) measurement. The results suggest that maternal influences contribute to the growth of a distinct cranial base and to the magnitude of mandibular retrognathism of subjects with TS.

Lateral meningocele syndrome: Vertical transmission and expansion of the phenotype

Lateral meningoceles were first described by Lehman et al. [(1977); J Pediatr 90: 49-54] in a patient with other skeletal findings and distinctive craniofacial features. Subsequently, six more patients with the so-called lateral meningocele syndrome (LMS) have been reported. We describe the findings in three new cases and expand the phenotype. The existence of an affected mother and daughter supports the hypothesis that LMS is a dominant disorder affecting primarily the connective tissue.

Identification of a 3.0-kb Major Recombination Hotspot in Patients with Sotos Syndrome Who Carry a Common 1.9-Mb Microdeletion

Sotos syndrome (SoS) is a congenital dysmorphic disorder characterized by overgrowth in childhood, distinctive craniofacial features, and mental retardation. Haploinsufficiency of the NSD1 gene owing to either intragenic mutations or microdeletions is known to be the major cause of SoS. The common approximately 2.2-Mb microdeletion encompasses the whole NSD1 gene and neighboring genes and is flanked by low-copy repeats (LCRs). Here, we report the identification of a 3.0-kb major recombination hotspot within these LCRs, in which we mapped deletion breakpoints in 78.7% (37/47) of patients with SoS who carry the common microdeletion. The deletion size was subsequently refined to 1.9 Mb. Sequencing of breakpoint fragments from all 37 patients revealed junctions between a segment of the proximal LCR (PLCR-B) and the corresponding region of the distal LCR (DLCR-2B). PLCR-B and DLCR-2B are the only directly oriented regions, whereas the remaining regions of the PLCR and DLCR are in inverted orientation. The PLCR, with a size of 394.0 kb, and the DLCR, with a size of of 429.8 kb, showed high overall homology (approximately 98.5%), with an increased sequence similarity (approximately 99.4%) within the 3.0-kb breakpoint cluster. Several recombination-associated motifs were identified in the hotspot and/or its vicinity. Interestingly, a 10-fold average increase of a translin motif, as compared with the normal distribution within the LCRs, was recognized. Furthermore, a heterozygous inversion of the interval between the LCRs was detected in all fathers of the children carrying a deletion in the paternally derived chromosome. The functional significance of these findings remains to be elucidated. Segmental duplications of the primate genome play a major role in chromosomal evolution. Evolutionary study showed that the duplication of the SoS LCRs occurred 23.3-47.6 million years ago, before the divergence of Old World monkeys.

Interstitial deletion of the long arm of chromosome 5 in a boy with multiple congenital anomalies and mental retardation: Molecular characterization of the deleted region to 5q22.3q23.3

Interstitial deletions of the middle portion of the long arm of chromosome 5 are relatively rare. So far, only 36 cases have been reported. Because of the repetitive banding pattern of this region, the extent and localization of the deleted segment has not been well characterized in the majority of reported cases. This has complicated attempts to establish a definite karyotype-phenotype correlation. We report a further case with a de novo interstitial deletion of the region 5q?15 to 5q?22 identified by standard karyotype analysis. The proband presented with failure to thrive, developmental delay, distinct craniofacial dysmorphic features, and associated structural anomalies (amongst them cleft palate, iris colobomata, and horseshoe kidney, which have previously been reported in 5q deletion cases). In addition, this child had an Arnold-Chiari type I malformation that required surgical decompression. FISH studies using BAC clones spanning the 5q15 to 5q22 region revealed that these were all present in both homologues. Use of more distal clones allowed delineation of the deleted region to 5q22.3q23.3 and to narrow down the breakpoints to approximately 200 kb. The 14 Mb deleted region contains about 60 genes but, with the possible exception of FBN2 and DMXL1, there are no obvious candidate genes for the specific components of the phenotype. This case illustrates the discrepancy between cytogenetic and molecular techniques in trying to delineate 5q interstitial deletions. Molecular studies need to be performed on these patients, to establish genotype-phenotype correlation and to understand the role and influence of genes in this region.

Post-natal size and morphology of the sella turcica in Williams syndrome

Williams syndrome (WS) is a rare congenital disorder with distinctive craniofacial features, cardiovascular abnormalities, mental retardation, and behaviour characteristics. The purpose of this study was to investigate the size and morphology of the sella turcica on profile cephalograms in a group of individuals with WS. The material consisted of radiographic cephalograms of 62 Norwegian children, adolescents, and adults with an age range of 4.7-44.4 years. The length, depth, and diameter of the sella turcica were measured and the mean values were compared with normal reference material from the Oslo University Craniofacial Growth Archive. In total, the two-dimensional size of the sella turcica in the WS group was smaller in length, depth, and diameter compared with the control group, but only occasionally reached a significance level of 5 per cent (Student's t-test). The morphology of the sella turcica was assessed and five different morphological types were identified; oblique anterior wall, extremely low sella turcica, sella turcica bridging, irregularity (notching) in the posterior part of the dorsum sellae, and pyramidal shape of the dorsum sellae. The occurrence of these morphological types was more frequent in the WS subjects compared with the reference material, except for sella turcica bridging, which was equally frequent. The females with WS had more dysmorphic sella turcicas than males. This study has demonstrated morphological aberrations in the sella turcica in Norwegian individuals with WS, which should be further elucidated in future research and combined with neurological andendocrinological investigations.

Genetics of Sotos syndrome.

Sotos syndrome (SoS) (OMIM #117550) is a childhood overgrowth syndrome characterized by excessive growth, distinctive craniofacial features, developmental delay, and advanced bone age. Recently, haploinsufficiency of the NSD1 gene has been identified as the major cause of SoS, with intragenic mutations or submicroscopic microdeletions being found in about 60 to 75% of clinically diagnosed patients with SoS. Recent reports provided much information about the genetic background of SoS, the NSD gene family, and genotype-phenotype correlation. They also added new perspectives in the discussion about a possible association between SoS and neoplasia. This review focuses on recent genetic developments in SoS. Clinical features and associated anomalies are reviewed in relation to possible functional roles of NSD1. Genotype-phenotype correlation between patients with SoS harboring either intragenic mutations or microdeletions is discussed as well as their implication for possible revision of the diagnostic criteria of SoS. Furthermore, future prospects in genetic research of SoS are presented.

Association of Distinct Craniofacial Features in Nonsyndromic Cleft Lip and Palate Family Members

Abstract Objective: To assess the relationship of distinct craniofacial features among family members with cleft lip and palate (CLP). Methods: Lateral cephalometric and anthropometric measurements of the members of 28 Costa Rican families with CLP were analyzed. The distinct craniofacial features in subjects with CLP were identified by comparing their craniofacial measurements with published normative values. The presence of these features was assessed in the unaffected family members. Regression coefficients were computed to evaluate the association of the distinct craniofacial measurements between parents and their offspring with and without CLP. Results: The male and female subjects with CLP were characterized by shortened head (HL), anterior cranial base (S-N), and palatal length (ANS-PNS, A-PNS) measurements as well as hyperdivergent angle of S-N plane to palatal plane (<SN-PP). All unaffected family members also had shortened S-N and ANS-PNS measurements and mothers of affected daughters also short...