e-ISSN 1941-5923 © Am J Case Rep, 2019; 20: 1159-1169 DOI: 10.12659/AJCR.914924 Received: 2019.01.02 Accepted: 2019.05.26 Complications of Insufficient Dura and Blood Published: 2019.08.08 Loss During Surgical Intervention in Shprintzen- Goldberg Syndrome: A Case Report Authors’ Contribution: ABCDEF 1 Gabrielle R. O’Dougherty 1 Boler-Parseghian Center for Rare and Neglected Diseases, Department of Study Design A CD 2 Daniel H. Fulkerson Biological Sciences, University of Notre Dame, Notre Dame, IN, U.S.A. Data Collection B 2 Memorial Hospital South Bend, South Bend, IN, U.S.A. Statistical Analysis C B 2 Melissa Kern Data Interpretation D ABCDEF 1 Kasturi Haldar Manuscript Preparation E ABDEF 1 Barbara Calhoun Literature Search F Funds Collection G Corresponding Author: Barbara Calhoun, e-mail: [email protected] [email protected] Conflict of interest: None declared Source of support: Center for Rare and Neglected Diseases Summer Undergraduate Research Fellowship supported by the Bill and Lisa Powers Family Fund Patient: Female, 9 Final Diagnosis: Mandibular hypoplasia secondary to Shprintzen-Goldberg Syndrome Symptoms: Difficulty swallowing Medication: — Clinical Procedure: Bilateral mandibular osteotomy and distraction for mandibular hypolasia Specialty: Neurosurgery Objective: Rare disease Background: Shprintzen-Goldberg syndrome (SGS) is an extremely rare collagenopathy, most often caused by autosomal- dominant mutations in the SKI proto-oncogene, which is a component of the transforming growth factor beta (TGF-b) signaling pathway. Approximately 50–60 cases of SGS have been recorded in the literature worldwide since its discovery in 1982. This collagen disorder affects bone and vascular development throughout the body, resulting in craniosynostosis, scoliosis, chest deformities, and aortic root dilation. Patients may have problems in the central nervous system, including Chiari 1 malformation, hydrocephalus, and dilation of the lateral ven- tricles. Unfortunately, the symptoms of SGS closely parallel those of related collagenopathies involving muta- tions in the TGF-b signaling pathway, which makes accurate diagnosis difficult without genetic testing, espe- cially in cases with complex presentation. Case Report: In this report we present the unique and complex disease manifestations in a 9-year-old girl with SGS. The pa- tient had severe cervical spinal instability that resolved after surgical occipital-C4 fusion with an autograft from the rib. Midface distraction surgery was used to treat the patient’s craniosynostosis and related facial deformities. This surgery was complicated by loss of 750 mL of blood due to insufficient dura and prominent vasculature. Conclusions: Connective tissue symptoms associated with SGS can involve dural and vascular problems, as seen in this case report. Thus, the risk of extreme blood loss should be anticipated any time midface distraction surgery is per- formed on an SGS patient. Continued research is needed to define how this case relates to the SGS patient population. MeSH Keywords: Craniosynostosis • DiGeorge Syndrome • Dura Mater • Osteogenesis, Distraction • Spinal Cord Compression Abbreviations: SGS – Shprintzen-Goldberg Syndrome; LDS – Loeys-Dietz Syndrome; MRI – magnetic resonance imaging; CT scan – computerized axial tomography scan; CSF – cerebrospinal fluid Full-text PDF: https://www.amjcaserep.com/abstract/index/idArt/914924 2044 5 2 43 This work is licensed under Creative Common Attribution- Indexed in: [PMC] [PubMed] [Emerging Sources Citation Index (ESCI)] NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) [Web of Science by Clarivate] 1159 O’Dougherty G. et al.: Dural insufficiency in Shprintzen-Goldberg syndrome © Am J Case Rep, 2019; 20: 1159-1169 Background apnea [4]. Midface hypoplasia and its resultant problems are often addressed in SGS patients with surgical treatment in- Shprintzen-Goldberg syndrome (OMIM #182212) is an ultra- volving opening of the skull. However, such surgeries are ex- rare autosomal-dominant genetic collagenopathy. Common tremely risky in patients with collagen disorders affecting the characteristics include marfanoid body habitus, characteris- dura and surrounding vascularity. Thus, the prevalent connec- tic craniofacial abnormalities, craniosynostosis, severe scoli- tive tissue problems must be assessed prior to surgical inter- osis, rib abnormalities, intellectual disability, abdominal and vention in SGS patients. umbilical hernias, and aortic dilation. SGS is molecularly het- erogeneous, with mutations most often found in the R-SMAD binding region of exon 1 of the SKI (Sloan-Kettering Institute) Case Report gene. Mutations in this gene result in an overactive SMAD- dependent pathway of TGF-b signaling. This patient was a full-term baby, birth weight 8 pounds 11 ounces, born to a G5P5 35-year-old mother. The pregnancy was The proto-oncoprotein SKI normally inhibits SMAD proteins by complicated by spotting at 7 weeks, difficulty picking up heart- preventing them from entering the nucleus to transcribe the beat at 19 weeks, and a 2-vessel umbilical cord. Although the TGF-b gene. The TGF-b pathway is essential for cell growth, vaginal delivery was relatively easy, the baby had a fractured proliferation, and programmed cell death. Its dysregulation re- clavicle at birth. The patient’s dysmorphic facial features in- sults in many of the cardiovascular and connective tissue de- cluded frontal bossing, low-set ears, hairy ear lobes, and facial formities seen in SGS [1]. Less frequently, SGS patients have features resembling trisomy 21. The patient displayed moder- mutations in the fibrillin 1 (FBN1) gene, which also codes for ate hypotonia, loose hips, and significant head lag. These con- a TGF-b regulatory protein. Mutations in other proteins on this cerns led to immediate transfer from the birthing center to the pathway can also result in excess activity, leading to similar local hospital and subsequent transfer via life-flight to the re- phenotypic presentations as seen in Marfan and Loeys-Dietz gional hospital. Karyotype was normal (46XX) and Fluorescence syndromes [2]. There is often an extensive delay preceding in situ hybridization (FISH) assays were negative for all triso- SGS diagnosis because it is extremely difficult to distinguish mies. Upon discharge, the patient had difficulties feeding and between these related collagenopathies. Delay of diagnosis in gaining weight, resulting in 3 hospitalizations for failure to SGS can have fatal consequences, as will be discussed later thrive during the first year. Facial deformities and hypotonia in this report. contributed to her inability to innervate muscles needed for eating and swallowing. After supplementary high-calorie for- Fortunately, the differential expressions of various proteins mula and breastfeeding showed limited success, a gastrosto- in the TGF-b pathway lead to slight differences between re- my tube (G-tube) was placed at 4 months. Adequate caloric lated collagenopathies. For example, aortic abnormalities are intake and expected growth for age were attained. G-tube usually milder in SGS than in Loeys-Dietz syndrome because feedings continue to be the primary form of nutrition to date. the SKI gene is expressed less pervasively in the aorta than are TGF-b receptor genes[1]. Moreover, intellectual disability Many of the patient’s symptoms corresponded with collagen- appears in SGS patients more often than in Loeys-Dietz pa- related disorders. Observed bony abnormalities included cervi- tients [1]. The present patient’s unique presentation of SGS cal spinal instability, 13 pairs of ribs, recurrent left knee sublux- most notably involves severe cervical spinal cord compres- ation, coxa valga, contractures, joint hyperflexibility, and focal sion, abnormal facial vasculature, and insufficient dura mater. reversal of lordosis at T12–L1. Finger abnormalities included camptodactyly, clinodactyly, hypoplastic thumbs, and arachno- The dura mater is the outermost layer of the meninges, which dactyly. This patient exhibited an asymmetric chest deformity provides a protective covering for the brain and spinal cord. involving both the pectus excavatum and carinatum. Notable The dura mater forms a barrier between cerebrospinal fluid craniofacial abnormalities included craniosynostosis, midface and blood. Thus, cerebrospinal fluid will leak if the dura is hypoplasia, exophthalmos, hypertelorism, ptosis, lagophthalmos, compromised. Cerebrospinal fluid leakage is a major neu- low-set ears, retrognathia, and a high narrow palate. At 2 years, rosurgical complication that can result in pneumocephalus, the patient was diagnosed with obstructive sleep apnea and meningitis, improper wound healing, and infections of the prescribed continuous positive airway pressure (CPAP), which graft-bone or epidural space [3]. Our patient presented with improved energy and progress with developmental milestones insufficient dura, resulting in CSF leakage during a combina- (see Table 1 for a full list of patient symptoms). tion Monobloc advancement and cranial vault remodeling sur- gery aimed to treat midface hypoplasia. Midface hypoplasia This patient was tested for Loeys-Dietz syndrome, otopalat- is common among SGS patients and can result in lagophthal- odigital syndrome, Sticklers syndrome, Zellweger syndrome, mos, obstruction of the upper airway, and obstructive sleep Marshall-Smith syndrome, and Marshall syndrome prior to This work is licensed under Creative Common Attribution- Indexed in: [PMC] [PubMed]