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Keywords:

  • Petty syndrome;
  • Fontaine–Farriaux syndrome;
  • laminopathy;
  • progeria;
  • craniosynostosis;
  • nail hypoplasia;
  • lipodystrophy

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. CLINICAL REPORTS
  5. DISCUSSION
  6. CONCLUSIONS
  7. REFERENCES

In 1990, Petty et al. described two patients representing a novel syndrome with “congenital progeriod” features and neither had classical progeria nor Wiedemann–Rautenstrauch syndrome, though many findings were overlapping. One of the cases had previously been described by Dr. Wiedemann in 1948. The key features of Petty syndrome include pre and postnatal growth restriction, decreased subcutaneous fat with loose skin, enlarged fontanelle with underdeveloped calvarium, coronal synostosis, unruly hair pattern with non-uniform distribution, prominent eyebrows, umbilical hernia, distal digital hypoplasia, and normal or near normal development. Significant overlap to other syndromes, particularly the Fontaine–Farriaux syndrome, is apparent. In 2004, Ardinger postulated that Petty syndrome, like classical progeria, might be secondary to a defect in the lamin A/C (LMNA) gene. The purpose of this paper is to describe two new unrelated cases of this unique syndrome that further delineate the phenotype, compare to phenotypically similar syndromes, and postulate that Petty syndrome could represent a new laminopathy. In addition, evidence suggesting that the Petty syndrome and Fontaine–Farriaux syndromes are variable expressions of the same condition is discussed. © 2010 Wiley-Liss, Inc.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. CLINICAL REPORTS
  5. DISCUSSION
  6. CONCLUSIONS
  7. REFERENCES

In 1990, Petty et al. described two patients comprising representing a new syndrome with “congenital progeriod” features. Neither individual represented classical progeria nor Wiedemann–Rautenstrauch syndrome, though many of their findings were overlapping. Notably one of the cases had previously been described by Dr. Wiedemann in 1948. Since that time, there have been several other published cases of congenital or neonatal progeria though little connection to the Petty cases has been made. In 2009, a new case was reported of Petty syndrome comparing the phenotype to conditions associated with premature aging [Delgado-Luengo et al., 2009]. Similarly, Fontaine–Farriaux syndrome was described in a child with craniosynostosis, patchy lipodystrophy, abnormal hair patterns and brain malformations [Fontaine et al., 1977]. Since the original descriptions of these two syndromes, there have been reports suggesting phenotypic overlap between them [Braddock et al., 2008; Castori et al., 2009]. In 2004, Ardinger postulated that Petty syndrome, like progeria itself, might be secondary to a defect in the lamin A/C (LMNA) gene.

The purpose of this paper is to describe two new unrelated patients with this unique syndrome that further delineate the phenotype, compare them to phenotypically similar syndromes, and postulate that Petty syndrome could represent a new laminopathy. In addition, evidence suggesting the Petty syndrome and Fontaine–Farriaux syndromes are variable expressions of the same condition is presented.

CLINICAL REPORTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. CLINICAL REPORTS
  5. DISCUSSION
  6. CONCLUSIONS
  7. REFERENCES

Patient 1

This patient was a female born at term to a 29-year-old G2P2 woman following a pregnancy complicated by IUGR, unusual shaped head and shortened long bones noted on prenatal ultrasound. Birth weight was 1,640 g, length 42.2 cm and OFC 28.5 cm (all <3rd centile). On examination sutures were widely patent from nasal root to the occiput with an overlying cutaneous vascular malformation. The calvarium was poorly ossified. There was an unusual hair pattern, sparse interrupted eyebrows, small low posteriorly rotated ears, short palpebral fissures, and downturned corners of the mouth. She had a large umbilical hernia, hypoplastic labia majora and little subcutaneous fat with loose and wrinkled skin throughout (Fig. 1). In addition, there was both distal digital and nail hypoplasia on all digits.

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Figure 1. Patient 1 at 10 weeks of age. Note characteristic facies with unusual hair and eyebrow pattern, lipodystrophy with loose skin, umbilical hernia, and nail hypoplasia.

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By 4 months of age her growth remained poor with length 51.8 cm, weight 2.86 kg and head circumference 35.0 cm, all still well below the 3rd centile. Examination then showed that she was alert and vocalizing. She had a very unruly hair pattern and there was a low anterior hairline and a “tuft” of hair anteriorly followed by a large gap before the parietal hair began. The cranial defect was large with palpable coronal sutures. Palpebral fissures were short and upslanting. Sclerae were blue. Eyebrows were arched with an interruption in the middle portion and flaring at that site. Ears were low-set and posteriorly rotated. There was a high nasal bridge and small nose. Philtrum was attenuated. Palate was intact with a prominent secondary alveolar ridge. Chest was noteworthy for generalized lipodystrophy with inverted nipples. There was a large umbilical hernia and lack of muscle tone over the abdomen. Genitalia revealed hypoplastic labia majora. The extremities had distal digital hypoplasia bilaterally with deep palmar and plantar creases. There was aplasia of the fingernails on the right 2nd, 4th, and 5th digits and left 4th and 5th digits with hypoplastic nails on the other digits. There was bilateral 4–5 soft tissue syndactyly of the toes with deep-set nails on the first toe and absent nails on the 3rd, 4th, and 5th toes bilaterally. There were multiple vascular malformations in separate locations over the spine as well as a large vascular malformation extending from the glabellar region over the cranium to the occiput and neck. At 5 months, her neurodevelopment was noted to be normal except for feeding difficulties. After having a gastrostomy placed she was noted to have idiopathic pulmonary hypertension, a patent ductus arteriosus, and a small secundum ASD. Surgery to close the patent ductus arteriosus did not alleviate the pulmonary hypertension and her respiratory condition worsened despite medical management. She expired at 7 months secondary to respiratory failure due to chronic aspiration and pulmonary hypertension.

An extensive workup during her lifetime revealed a normal 46, XX female karyotype with normal subtelomeric probes, and a normal chromosomal microarray analysis. Her radiographic skeletal survey was noteworthy for platyspondyly with undermineralization of the calvarium. Brain MRI indicated normal myelination with a partially absent corpus callosum with complete absence of the falx, and multiple bilateral intraparenchymal hemorrhages. A head CT scan revealed unilateral coronal synostosis. mRNA from patient fibroblasts was reverse-transcribed into cDNA in order to sequence the open reading frame encoded by LMNA. The patient was negative for the classical HGPS mutation [G608G; Eriksson et al., 2003]. We did find, however, that the patient contains a DNA mutation (C1698T in exon 10) that enhances formation of a transcript that lacks exon 11 (protein is denoted LaminA▵exon11).

Post mortem examination revealed a length of 55.0 cm, a crown rump length of 36.8 cm, a head circumference of 34.5 cm and weight of 2,800 g. Internal examination noted a secundum atrial septal defect with aberrant right subclavian artery tracking posterior to the esophagus, aberrant venous return with superior and inferior brachiocephalic veins, right ventricular hypertrophy and dilated pulmonary arteries with medial hypertrophy and moderate muscularization of intralobular aterioles. There was mild alveolar growth abnormality and arrested nephrogenic maturation. Examination of the central nervous system showed underdevelopment of the frontal and parietal bones with underossification of the calvarium and bicoronal synostosis. There was absence of the falx cerebri and superior sagittal sinus with a hypoplastic tentorium. The corpus callosum was present but there was asymmetry of the temporal lobe and cingulate gyrus exhibiting a larger right cortex. Electron microscopy demonstrated abnormal smooth and cardiac muscle nuclear contours, consistent with the nuclear blebbing observed in Hutchinson–Gilford Progeria syndrome (HGPS) (Fig. 2). Skeletal muscle (quadriceps) had moderate variation in myofiber size suggesting a myopathic process, though the significance was unclear. Electron microscopy of the CNS was not obtained (with permission of the author-father, we would like to point out that this child was the inspiration for the poem “Surf” [Myers-Benner, 2009]).

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Figure 2. Patient 1 electron micrograph. Note the abnormal nucleus with chromatin lining the nuclear membrane circumferentially.

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Patient 2

This boy was first seen at age 15 months for syndrome identification (Fig. 3). He was born to young nonconsanguineous parents after an uncomplicated pregnancy without known teratogenic exposures. There was normal fetal movement and an ultrasound at 20 weeks did not raise concerns about fetal growth or amniotic fluid volume. He was delivered at 38 weeks by cesarean when an ultrasound showed low amniotic fluid volume and small fetal size. Birth weight was 1,640 g, length was 42.5 cm and OFC was 27.5 cm (<3rd centile). Physical findings at birth included huge open confluent fontanels, a large amount of scalp hair on the sides of the head, small port wine stains on the head and back, excessive wrinkling of the skin, umbilical hernia, small genitalia with second degree hypospadias, undescended testes and distal digital hypoplasia with some missing nails. He required surgery for malrotation of the small intestine. He was discharged from the hospital at age 3 weeks taking breast milk by bottle. By 3 months, severe growth delay was noted and persisted despite increasing his caloric intake and gastrostomy tube. Tooth eruption began at 6 months and teeth were quite small with an unusual eruption pattern. The two lower central incisors were exfoliated at 21 months.

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Figure 3. Patient 2: Note unusual hair pattern and characteristic facies with unusual hair patterning, lack of subcutaneous tissue and abnormal ear in both frontal (A) and lateral (B) views.

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At 15 months, exam was remarkable for a length at the 50th centile for 8 months while weight was average for a 3-month-old. He was alert and lively with several single words and easily pulled himself to a stand on the exam table. Head circumference was at the 50th centile for 6 months. The entire top of the skull was open with proximal closure of the coronal sutures, large forehead, bitemporal constriction, malar hypoplasia and a triangular face with a pointed chin. Scalp hair was coarse and unruly with several hair whorls. The eyes appeared sunken due to lack of support from the superior wall of the orbit with very long dark lashes and thick brows. Ears were small and posteriorly rotated with small lobes. The nose had a prominent tip which was overhanging, and there was a thin upper lip vermilion with a high palate with tiny teeth. The skin was thin and translucent over most of the body with fine wrinkles over the face and neck. Skin over the extremities was slightly thicker with a small amount of subcutaneous tissue. Dimples were noted on shoulders and lateral knees. Nipples were underdeveloped and there was significant hypertrichosis over the back. A vascular stain over the spine and sacral dimples were present. A large umbilical hernia was present. Limbs were thin with hyperextensible elbows and knobby knees. There was distal hypoplasia of all digits with absent nails on the 3rd, 4th, 5th fingers and 5th toes with hypoplastic nails on all other digits. Mild 2–3 and 4–5 toe syndactyly was present.

Although he was generally healthy, a number of medical issues were identified. He had small facial bones with a turribrachycephalic head. Premature closure of the proximal coronal sutures with wide open anterior fontanel led to cranial re-shaping surgery at age 19 months. He had GE reflux treated medically, hyperopia with exotropia and a lower eyelid entropion treated surgically. He presented with a fever at 23 months, rapidly declined and died within 24 hr with pneumococcal sepsis. Autopsy was not performed.

Extensive laboratory evaluation returned normal results including karyotype, FGFR gene analysis, sweat chloride, thyroid function, plasma amino acids, urine organic acids, insulin level, lactate, pyruvate, IGF-1, vitamin B12, folate, carnitine and acylcarnitine. Glucose was low with prolonged fasting at 12 months and cholesterol and triglycerides were elevated after a 4 hr fast at 17 months. Fibroblast testing for defects of pyruvate metabolism and electron transport chain complex disorders was negative.

Skeletal survey at 14 months identified a bone age in the low normal range, hypoplastic distal phalanges for digits 1 and 2 and absent distal phalanges on digits 3, 4, and 5 on both hands and feet. Echocardiogram, head ultrasound, MRI of the brain and lumbar spine were all normal. Skull CT showed underdevelopment of the cranial bones with occipital flattening. A renal ultrasound showed some mild left pelvic fullness without hydronephrosis and normal right kidney.

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. CLINICAL REPORTS
  5. DISCUSSION
  6. CONCLUSIONS
  7. REFERENCES

Syndromes associated with premature aging are frequently referred to as “progeroid.” These conditions are manifest by normal clinical phenotypes at birth with subsequent rapid acceleration of the aging process. The most common of these is the Hutchinson–Gilford Progeria syndrome (HGPS). There have been several “progeroid” syndromes subsequently reported with a congenital phenotype and often referred to a congenital HGPS or lethal mandibuloacral dysplasia (MAD). This group also includes reported cases of Petty syndrome, Wiedemann–Rautenstrauch syndrome and Fontaine–Farriaux syndrome. Syndromes such as Yunis–Varon and DOOR also have some phenotypic overlap. However, the use of the term congenital or neonatal progeria or even “progeriod” is both misleading and inaccurate. These individuals are born with a distinctive facies with lack of subcutaneous tissues and underdeveloped facial bone structure rather than having prematurely aged in utero.

The two cases described by Petty et al. 1990 had pre- and postnatal growth deficiency, markedly diminished subcutaneous fat (lipodystrophy), sparse and unusually patterned hair, distal digital hypoplasia with nail hypoplasia, large open anterior fontanelle and both normal cognitive and motor development. A third case was also briefly discussed by Wiedemann 1992 shortly thereafter. More recently, Delgado-Luengo et al. 2009 described a 10-year-old boy with the same phenotype. Hypoplasia of the genitalia and soft tissue syndactyly were noted, as also seen in Patients 1 and 2. No mention was made of vascular malformations or craniosynostosis. Petty syndrome can be differentiated from Wiedemann–Rautenstrauch syndrome (WRS) by the lack of natal teeth, large hands/feet and severe developmental delay associated with WRS as well as the presence of distal digital hypoplasia and unusual hair patterns. There also appears to be some overlap of features between Petty syndrome and mandibuloacral dysplasia (MAD), though the lipodystrophy, distal digital hypoplasia, aged facial appearance and poor growth are all present at birth in Petty syndrome. A severe lethal neonatal MAD has been reported [Seftel et al., 1996] which has some overlap with Petty syndrome but the craniofacial phenotype is different.

A related condition, Fontaine–Farriaux syndrome, was first described in 1977 [Fontaine et al., 1977] in a child with patchy lipodystrophy, craniosynostosis, disorganized hair patterns, distal phalangeal hypoplasia, anonychia, hypoplastic abdominal wall musculature, lissencephaly with periventricular nodular heterotopia and severe mental retardation. A second case was reported by Priolo et al. 2001 though despite lipodystrophy and craniosynostosis, the absence of anonychia and abdominal wall hypoplasia suggests that this represents a separate entity. However Castori et al. 2009 reported a neonate with an almost identical phenotype to the original report. This case had generalized lipodystrophy rather than patchy distribution of lipodystrophy, abdominal wall hypoplasia, and severe CNS malformations. He expired on the first day of life. These features are also strikingly similar to those seen in Petty syndrome with the exception of the lipodystrophy being “patchy” rather than diffuse in the original description by Fontaine et al. 1977, craniosynostosis and the report of severe mental retardation. Subsequently, single case reports by Faivre et al. 1999 and Rodriguez et al. 1999 of “neonatal HGPS” overlap significantly with the cases described by Petty and most likely represent the same condition. In 2008, Braddock et al. presented a case of Petty syndrome with severe IUGR, bicoronal synostosis, large contiguous fontanelles, unusual hairlines with prominent eyebrows, lax skin especially around the neck and hands, large umbilical hernia, hypoplastic labia majora, distal digital hypoplasia with absent nails on the 4th and 5th digits, but normal neurological exam. CT scan showed left frontoparietal punctate densities though cognitive development was normal. Initially a diagnosis of Fontaine–Farriaux had been suggested, though based upon the significant clinical overlap and normal development a subsequent diagnosis of Petty syndrome was made.

The two patients described in this report, as well as the patient presented by Braddock et al. 2008 have clinical features which overlap both Petty syndrome and Fontaine–Farriaux syndrome. The salient features of these conditions are set forth in Table I. The recent reports of Braddock et al. 2008, Castori et al. 2009 and Delgado-Luengo et al. 2009 are also included for comparison. Although both of the cases described herein have evidence of craniosynostosis, they both lack the major CNS malformations or developmental disorders described in Fontaine–Farriaux. In addition, the lipodystrophy in the present cases is clearly not “patchy” in its appearance but rather diffuse. It would appear that these two cases resemble Petty syndrome. Likewise, the reported case by Braddock et al. 2008, despite an earlier diagnosis of Fontaine–Farriaux, most likely represents a bridge between these two syndromes (Table I). Furthermore, the case of Castori et al. 2009 also noted generalized lipodystrophy with major CNS malformations, further associating these two syndromes. Due to this significant overlap, we postulate that Petty syndrome and Fontaine–Farriaux syndrome represent a spectrum of the same disorder or are possibly allelic. The most significant differences, which are of utmost importance to families, are the CNS morphologic and functional findings, which appear less severe in Petty syndrome.

Table I. Comparisons of Cases With Petty and Fontaine–Farriaux Syndromes
FeaturePatient 1Patient 2Braddock et al. 2008Petty et al. 1990Delgado-Luengo et al. 2009Fontaine et al. 1977Castori et al. 2009
  1. (+) presence of clinical finding, (−) absence of clinical finding, (?) unknown, (NA) not applicable.

Premature “aged” appearance+++++++
Growth retardation+++++++
Lipodystrophy+++++++
Craniosynostosis+++?++
Thin calvarium++++?
Large fontanelle+++++++
Scalp vascular malformation+++++
Thick eyebrows+++++?
Unusual hair pattern+++++++
Small ears++++++
Midface hypoplasia+++++++
Distal digit hypoplasia+++++++
Nail hypoplasia+++++++
Umbilical hernia++++++
Abdominal muscle hypoplasia+++++
Genital hypoplasia/cryptorchidism++++++
Congenital heart defects++
CNS abnormalities++++
Dev delay/MR+NA

Hutchinson–Gilford progeria syndrome is caused by a 608G>G point mutation in exon 11 of the lamin A/C gene (LMNA). More than ten other conditions have been described with mutations in the LMNA gene. As a group these are referred to as laminopathies, though phenotypic expression is highly variable, ranging from HGPS to mandibuloacral dysplasia (MAD), Emery–Dreifuss muscular dystrophy, Charcot–Marie–Tooth, and dilated cardiomyopathy type 1A. In all of these conditions, however, the findings are normal at birth with progressive changes occurring in childhood or later. Restrictive dermopathy, a neonatal lethal condition is also a laminopathy, but secondary to a defect in ZMPSTE24, a gene required for normal LaminA maturation. It has been postulated that Petty syndrome might actually represent a laminopathy with a congenital phenotype [Ardinger, 2005].

It is still unclear as to whether or not Petty syndrome definitively represents a laminopathy. From a phenotypic as well as genotypic standpoint, Case 1 clearly does not have classic HGPS. Although Lamin A/C testing was negative for the classical HGPS mutation (G608G), there was expression of a LMNA-derived mRNA that lacked exon 11 (protein is denoted LaminA▵exon11). The protein encoded by LaminA▵exon11 has a 90 amino acid deletion that is predicted to be sufficient to promote progeroid phenotypes at the cellular, tissue, and organ levels. Expression of LaminA▵exon11 in cultured cells induces nuclear morphology defects very similar to what has been observed in HGPS [Yang et al., 2008]. Moreover, the electron microscopy of cardiac, skeletal muscle and liver tissues from Case 1 revealed defects in nuclear morphology and chromatin organization, in which the chromatin is compressed against the nuclear membranes. On the cellular level this is suggestive of a laminopathy. These findings provide some support suggesting that Petty syndrome is a laminopathy closely related to progeria. It is also unlikely that this case is secondary to a defect in ZMPSTE24 as no accumulation of incompletely processed lamin A was identified. Other abnormalities affecting nuclear membrane and lamin formation need to be further investigated to definitively address this possibility.

CONCLUSIONS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. CLINICAL REPORTS
  5. DISCUSSION
  6. CONCLUSIONS
  7. REFERENCES

The two patients described herein have features most consistent with those described by Petty et al. 1990. The key features of Petty syndrome include pre- and postnatal growth restriction, decreased subcutaneous fat with loose skin, enlarged fontanelle with underdeveloped calvarium, coronal synostosis, unruly hair pattern with non-uniform distribution, prominent eyebrows, umbilical hernia, distal digital hypoplasia, and normal or near normal development. Although both patients have evidence of craniosynostosis, they do not appear to have the major CNS malformations nor the developmental disorders described in the prior cases of Fontaine–Farriaux syndrome. While it is possible that these are allelic conditions, the normal cognitive function described in Petty syndrome is significant and reassuring for families. However, the striking similarity to the known cases of Fontaine–Farriaux syndrome is more likely indicative that these conditions are indeed a single entity with variable expression. Further delineation of the relationship between this condition and previously described laminopathies is also indicated. The abnormal nuclear morphology viewed by electron microscopy and the presence of a LMNA mutation that gives rise to LaminA▵exon11 protein suggest that Petty syndrome could be a laminopathy. In addition, a comparison with other “progeroid” syndromes in the literature, particularly Wiedemann–Rautenstrauch, and mandibuloacral dysplasia, may identify other cases that are similar or have been misclassified.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. CLINICAL REPORTS
  5. DISCUSSION
  6. CONCLUSIONS
  7. REFERENCES
  • Ardinger HH. 2005. Proc Greenwood Genet Center 24: 142.
  • Braddock SR, Golabi M, Hall BD. 2008. Petty syndrome: Further delineation of a rare “old” syndrome. Presented at the 29th David W. Smith Workshop on Malformations and Morphogenesis.
  • Castori M, Silvestri E, Pedace L, Marseglia G, Tempera A, Antigoni I, Torricelli F, Majore S, Grammatico P. 2009. Fontaine–Farriaux syndrome: A recognizable craniosynostosis syndrome with nail, skeletal, abdominal, and central nervous system anomalies. Am J Med Genet Part A 149A: 21932199.
  • Delgado-Luengo WN, Petty EM, Solis-Anez E, Romel O, Delgado-Luengo J, Hernandez ML, Morales-Machin A, Borjas-Fuentes L, Zabala-Fernandez W, Gonzalez-Ferrer S, Pineda-Bernal L, Pardo-Govea T, Martinez-Basalo MC, Gonzalez R, Urdaneta K, Canizales J, Fleitas-Cabello H. 2009. Petty–Laxova–Wiedemann progeroid syndrome: Further phenotypical delineation and confirmation of a rare syndrome of premature aging. Am J Med Genet Part A 149A: 22002205.
  • Eriksson M, Brown WT, Gordon LB, Glynn MW, Singer J, Scott L, Erdos MR, Robbins CM, Moses TY, Berglund P, Dutra A, Pak E, Durkin S, Csoka AB, Boehnke M, Glover TW, Collins FS. 2003. Recurrent de novo point mutations in lamin A cause Hutchinson–Gilford progeria syndrome. Nature 423: 293298.
  • Faivre L, Khau Van Kien P, Madinier-Chappat N, Nivelon-Chevallier A, Beer F, LeMerrer M. 1999. Can Hutchinson–Gilford progeria syndrome be a neonatal condition? Am J Med Genet 87: 450.
  • Fontaine G, Farriaux JP, Blanckaert D, Lefebvre C. 1977. Un nouveau syndrome polymalformatif complexe. J Genet Hum 25: 109119.
  • Myers-Benner J. 2009. Surf: For those who care for dying children. Am J Med Genet Part A 149A: 301.
  • Petty EM, Laxova R, Wiedemann H-R. 1990. Previously unrecognized congenital progeroid disorder. Am J Med Genet 35: 383387.
  • Priolo M, De Toni T, Baffico M, Cama A, Seri M, Cusano R, Costabello L, Fondelli P, Capra V, Silengo M, Ravazzolo R, Lerone M. 2001. Fontaine–Farriaux craniosynostosis: Second report in the literature. Am J Med Genet 100: 214218.
  • Rodriguez JI, Pérez-Alonso P, Funes R, Pérez-Rodriguez J. 1999. Lethal neonatal Hutchinson–Gilford progeria syndrome. Am J Med Genet 82: 242248.
  • Seftel MD, Wright CA, Po PLW, De Ravel TJL. 1996. Lethal neonatal mandibuloacral dysplasia. Am J Med Genet 66: 5254.
  • Wiedemann H-R. 1992. Newly recognized congenital progeriod disorder. Am J Med Genet 42: 857.
  • Yang CS, Braddock SR, Paschal BM. 2008. unpublished observations.