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Neurodevelopmental disorder with craniofacial dysmorphism and skeletal defects(NEDCDS)

MedGen UID:
1824008
Concept ID:
C5774235
Disease or Syndrome
Synonym: NEDCDS
 
Gene (location): HNRNPH1 (5q35.3)
 
Monarch Initiative: MONDO:0859301
OMIM®: 620083

Definition

Neurodevelopmental disorder with craniofacial dysmorphism and skeletal defects (NEDCDS) is characterized by global developmental delay, severely impaired intellectual development with poor or absent speech, characteristic facial features, and variable skeletal abnormalities. Additional features include feeding difficulties, inability to walk or walking with an abnormal gait, and cerebellar or other abnormalities on brain imaging (Reichert et al., 2020). [from OMIM]

Clinical features

From HPO
Cryptorchidism
MedGen UID:
8192
Concept ID:
C0010417
Congenital Abnormality
Cryptorchidism, or failure of testicular descent, is a common human congenital abnormality with a multifactorial etiology that likely reflects the involvement of endocrine, environmental, and hereditary factors. Cryptorchidism can result in infertility and increases risk for testicular tumors. Testicular descent from abdomen to scrotum occurs in 2 distinct phases: the transabdominal phase and the inguinoscrotal phase (summary by Gorlov et al., 2002).
Horseshoe kidney
MedGen UID:
65140
Concept ID:
C0221353
Congenital Abnormality
A connection of the right and left kidney by an isthmus of functioning renal parenchyma or fibrous tissue that crosses the midline.
Congenital posterior urethral valve
MedGen UID:
451008
Concept ID:
C0238506
Congenital Abnormality
A developmental defect resulting in an obstructing membrane in the posterior male urethra.
Hypospadias
MedGen UID:
163083
Concept ID:
C0848558
Congenital Abnormality
Abnormal position of urethral meatus on the ventral penile shaft (underside) characterized by displacement of the urethral meatus from the tip of the glans penis to the ventral surface of the penis, scrotum, or perineum.
Penile hypospadias
MedGen UID:
305577
Concept ID:
C1691215
Congenital Abnormality
Location of the urethral opening on the inferior aspect of the penis.
Arachnodactyly
MedGen UID:
2047
Concept ID:
C0003706
Congenital Abnormality
Abnormally long and slender fingers ("spider fingers").
Clubbing of fingers
MedGen UID:
3129
Concept ID:
C0009080
Finding
Terminal broadening of the fingers (distal phalanges of the fingers).
Talipes valgus
MedGen UID:
57757
Concept ID:
C0152236
Congenital Abnormality
Outward turning of the heel, resulting in clubfoot with the person walking on the inner part of the foot.
Knee dislocation
MedGen UID:
102364
Concept ID:
C0159970
Injury or Poisoning
Slippage of the FEMUR off the TIBIA.
Coxa valga
MedGen UID:
116080
Concept ID:
C0239137
Finding
Coxa valga is a deformity of the hip in which the angle between the femoral shaft and the femoral neck is increased compared to age-adjusted values (about 150 degrees in newborns gradually reducing to 120-130 degrees in adults).
Hand clenching
MedGen UID:
65994
Concept ID:
C0239815
Finding
An abnormal hand posture in which the hands are clenched to fists. All digits held completely flexed at the metacarpophalangeal and interphalangeal joints. In prenatal sonography of the fetal clenched hand, the index finger overlaps a clenched fist formed by the other digits. The proximal interphalangeal articulation of the index finger is flexed and ulnarly deviated, and the thumb is adducted.
Clinodactyly of the 5th finger
MedGen UID:
340456
Concept ID:
C1850049
Congenital Abnormality
Clinodactyly refers to a bending or curvature of the fifth finger in the radial direction (i.e., towards the 4th finger).
Clubbing of toes
MedGen UID:
854352
Concept ID:
C3887489
Anatomical Abnormality
Terminal broadening of the toes (distal phalanges of the toes).
Short stature
MedGen UID:
87607
Concept ID:
C0349588
Finding
A height below that which is expected according to age and gender norms. Although there is no universally accepted definition of short stature, many refer to "short stature" as height more than 2 standard deviations below the mean for age and gender (or below the 3rd percentile for age and gender dependent norms).
Failure to thrive
MedGen UID:
746019
Concept ID:
C2315100
Disease or Syndrome
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
Feeding difficulties
MedGen UID:
65429
Concept ID:
C0232466
Finding
Impaired ability to eat related to problems gathering food and getting ready to suck, chew, or swallow it.
Gastroesophageal reflux
MedGen UID:
1368658
Concept ID:
C4317146
Finding
A condition in which the stomach contents leak backwards from the stomach into the esophagus through the lower esophageal sphincter.
Low-set ears
MedGen UID:
65980
Concept ID:
C0239234
Congenital Abnormality
Upper insertion of the ear to the scalp below an imaginary horizontal line drawn between the inner canthi of the eye and extending posteriorly to the ear.
Small earlobe
MedGen UID:
334587
Concept ID:
C1842680
Finding
Reduced volume of the earlobe.
Cerebellar ataxia
MedGen UID:
849
Concept ID:
C0007758
Disease or Syndrome
Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- or overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).
Dystonic disorder
MedGen UID:
3940
Concept ID:
C0013421
Sign or Symptom
An abnormally increased muscular tone that causes fixed abnormal postures. There is a slow, intermittent twisting motion that leads to exaggerated turning and posture of the extremities and trunk.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterised by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Intellectual disability, severe
MedGen UID:
48638
Concept ID:
C0036857
Mental or Behavioral Dysfunction
Severe mental retardation is defined as an intelligence quotient (IQ) in the range of 20-34.
Tethered cord
MedGen UID:
36387
Concept ID:
C0080218
Disease or Syndrome
During normal embryological development, the spinal cord first occupies the entire length of the vertebral column but goes on to assume a position at the level of L1 due to differential growth of the conus medullaris and the vertebral column. The filum terminale is a slender, threadlike structure that remains after the normal regression of the distal embryonic spinal cord and attaches the spinal cord to the coccyx. A tethered cord results if there is a thickened rope-like filum terminale which anchors the cord at the level of L2 or below, potentially causing neurologic signs owing to abnormal tension on the spinal cord.
Colpocephaly
MedGen UID:
98131
Concept ID:
C0431384
Congenital Abnormality
Colpocephaly is an anatomic finding in the brain manifested by occipital horns that are disproportionately enlarged in comparison with other parts of the lateral ventricles.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Inability to walk
MedGen UID:
107860
Concept ID:
C0560046
Finding
Incapability to ambulate.
Cerebellar vermis hypoplasia
MedGen UID:
333548
Concept ID:
C1840379
Finding
Underdevelopment of the vermis of cerebellum.
Absent speech
MedGen UID:
340737
Concept ID:
C1854882
Finding
Complete lack of development of speech and language abilities.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
Hip dislocation
MedGen UID:
42455
Concept ID:
C0019554
Injury or Poisoning
Displacement of the femur from its normal location in the hip joint.
Hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.
Osteopenia
MedGen UID:
18222
Concept ID:
C0029453
Disease or Syndrome
Osteopenia is a term to define bone density that is not normal but also not as low as osteoporosis. By definition from the World Health Organization osteopenia is defined by bone densitometry as a T score -1 to -2.5.
Retrognathia
MedGen UID:
19766
Concept ID:
C0035353
Congenital Abnormality
An abnormality in which the mandible is mislocalised posteriorly.
Scoliosis
MedGen UID:
11348
Concept ID:
C0036439
Disease or Syndrome
The presence of an abnormal lateral curvature of the spine.
Radial head subluxation
MedGen UID:
56213
Concept ID:
C0149977
Injury or Poisoning
Partial dislocation of the head of the radius.
Pectus carinatum
MedGen UID:
57643
Concept ID:
C0158731
Finding
A deformity of the chest caused by overgrowth of the ribs and characterized by protrusion of the sternum.
Joint hypermobility
MedGen UID:
336793
Concept ID:
C1844820
Finding
The capability that a joint (or a group of joints) has to move, passively and/or actively, beyond normal limits along physiological axes.
Metaphyseal widening
MedGen UID:
341364
Concept ID:
C1849039
Finding
Abnormal widening of the metaphyseal regions of long bones.
Malar flattening
MedGen UID:
347616
Concept ID:
C1858085
Finding
Underdevelopment of the malar prominence of the jugal bone (zygomatic bone in mammals), appreciated in profile, frontal view, and/or by palpation.
Small foramen magnum
MedGen UID:
348813
Concept ID:
C1861217
Finding
An abnormal narrowing of the foramen magnum.
Plagiocephaly
MedGen UID:
1825944
Concept ID:
C2081594
Finding
Asymmetric head shape, which is usually a combination of unilateral occipital flattening with ipsilateral frontal prominence, leading to rhomboid cranial shape.
Slender long bones with narrow diaphyses
MedGen UID:
436459
Concept ID:
C2675547
Finding
Reduced diameter of a long bone with a more pronounced reduction of the diameter of the diaphysis of the long bones.
Elbow dislocation
MedGen UID:
404765
Concept ID:
C2720437
Injury or Poisoning
Dislocation of the distal humerus out of the elbow joint, where the radius, ulna, and humerus meet.
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Blepharophimosis
MedGen UID:
2670
Concept ID:
C0005744
Congenital Abnormality
A fixed reduction in the vertical distance between the upper and lower eyelids with short palpebral fissures.
Dental crowding
MedGen UID:
11850
Concept ID:
C0040433
Finding
Changes in alignment of teeth in the dental arch
High forehead
MedGen UID:
65991
Concept ID:
C0239676
Finding
An abnormally increased height of the forehead.
High palate
MedGen UID:
66814
Concept ID:
C0240635
Congenital Abnormality
Height of the palate more than 2 SD above the mean (objective) or palatal height at the level of the first permanent molar more than twice the height of the teeth (subjective).
Open bite
MedGen UID:
78589
Concept ID:
C0266061
Anatomical Abnormality
Visible space between the dental arches in occlusion.
Mandibular prognathia
MedGen UID:
98316
Concept ID:
C0399526
Finding
Abnormal prominence of the chin related to increased length of the mandible.
Downslanted palpebral fissures
MedGen UID:
98391
Concept ID:
C0423110
Finding
The palpebral fissure inclination is more than two standard deviations below the mean.
Long face
MedGen UID:
324419
Concept ID:
C1836047
Finding
Facial height (length) is more than 2 standard deviations above the mean (objective); or, an apparent increase in the height (length) of the face (subjective).
Narrow nasal ridge
MedGen UID:
373404
Concept ID:
C1837761
Finding
Decreased width of the nasal ridge.
Highly arched eyebrow
MedGen UID:
358357
Concept ID:
C1868571
Finding
Increased height of the central portion of the eyebrow, forming a crescent, semicircular, or inverted U shape.
Nystagmus
MedGen UID:
45166
Concept ID:
C0028738
Disease or Syndrome
Rhythmic, involuntary oscillations of one or both eyes related to abnormality in fixation, conjugate gaze, or vestibular mechanisms.
Strabismus
MedGen UID:
21337
Concept ID:
C0038379
Disease or Syndrome
A misalignment of the eyes so that the visual axes deviate from bifoveal fixation. The classification of strabismus may be based on a number of features including the relative position of the eyes, whether the deviation is latent or manifest, intermittent or constant, concomitant or otherwise and according to the age of onset and the relevance of any associated refractive error.
Optic disc pallor
MedGen UID:
108218
Concept ID:
C0554970
Finding
A pale yellow discoloration of the optic disk (the area of the optic nerve head in the retina). The optic disc normally has a pinkish hue with a central yellowish depression.

Professional guidelines

PubMed

Battaglia A, Filippi T, Carey JC
Am J Med Genet C Semin Med Genet 2008 Nov 15;148C(4):246-51. doi: 10.1002/ajmg.c.30187. PMID: 18932224
Girirajan S, Vlangos CN, Szomju BB, Edelman E, Trevors CD, Dupuis L, Nezarati M, Bunyan DJ, Elsea SH
Genet Med 2006 Jul;8(7):417-27. doi: 10.1097/01.gim.0000228215.32110.89. PMID: 16845274

Recent clinical studies

Etiology

Yabumoto M, Kianmahd J, Singh M, Palafox MF, Wei A, Elliott K, Goodloe DH, Dean SJ, Gooch C, Murray BK, Swartz E, Schrier Vergano SA, Towne MC, Nugent K, Roeder ER, Kresge C, Pletcher BA, Grand K, Graham JM Jr, Gates R, Gomez-Ospina N, Ramanathan S, Clark RD, Glaser K, Benke PJ, Cohen JS, Fatemi A, Mu W, Baranano KW, Madden JA, Gubbels CS, Yu TW, Agrawal PB, Chambers MK, Phornphutkul C, Pugh JA, Tauber KA, Azova S, Smith JR, O'Donnell-Luria A, Medsker H, Srivastava S, Krakow D, Schweitzer DN, Arboleda VA
Mol Genet Genomic Med 2021 Oct;9(10):e1809. Epub 2021 Sep 14 doi: 10.1002/mgg3.1809. PMID: 34519438Free PMC Article
Michael Yates T, Ng OH, Offiah AC, Willoughby J, Berg JN; DDD Study, Johnson DS
Am J Med Genet A 2019 Jan;179(1):43-49. Epub 2018 Dec 17 doi: 10.1002/ajmg.a.60678. PMID: 30556256
Beleza-Meireles A, Hart R, Clayton-Smith J, Oliveira R, Reis CF, Venâncio M, Ramos F, Sá J, Ramos L, Cunha E, Pires LM, Carreira IM, Scholey R, Wright R, Urquhart JE, Briggs TA, Kerr B, Kingston H, Metcalfe K, Donnai D, Newman WG, Saraiva JM, Tassabehji M
Eur J Med Genet 2015 Sep;58(9):455-65. Epub 2015 Jul 20 doi: 10.1016/j.ejmg.2015.07.003. PMID: 26206081
Park JM, Kim HJ, Kim T, Chae HW, Kim DH, Lee MG
Int J Dermatol 2011 Feb;50(2):168-74. doi: 10.1111/j.1365-4632.2010.04639.x. PMID: 21244380
Ornoy A
Reprod Toxicol 2009 Jul;28(1):1-10. Epub 2009 Mar 13 doi: 10.1016/j.reprotox.2009.02.014. PMID: 19490988

Diagnosis

Fennell AP, Baxter AE, Berkovic SF, Ellaway CJ, Forwood C, Hildebrand MS, Kumble S, McKeown C, Mowat D, Poke G, Rajagopalan S, Regan BM, Scheffer IE, Stark Z, Stutterd CA, Tan TY, Wilkins EJ, Yeung A, Hunter MF
Am J Med Genet A 2022 Dec;188(12):3432-3447. Epub 2022 Aug 17 doi: 10.1002/ajmg.a.62950. PMID: 36367278
Yabumoto M, Kianmahd J, Singh M, Palafox MF, Wei A, Elliott K, Goodloe DH, Dean SJ, Gooch C, Murray BK, Swartz E, Schrier Vergano SA, Towne MC, Nugent K, Roeder ER, Kresge C, Pletcher BA, Grand K, Graham JM Jr, Gates R, Gomez-Ospina N, Ramanathan S, Clark RD, Glaser K, Benke PJ, Cohen JS, Fatemi A, Mu W, Baranano KW, Madden JA, Gubbels CS, Yu TW, Agrawal PB, Chambers MK, Phornphutkul C, Pugh JA, Tauber KA, Azova S, Smith JR, O'Donnell-Luria A, Medsker H, Srivastava S, Krakow D, Schweitzer DN, Arboleda VA
Mol Genet Genomic Med 2021 Oct;9(10):e1809. Epub 2021 Sep 14 doi: 10.1002/mgg3.1809. PMID: 34519438Free PMC Article
Mastrangelo M, Scheffer IE, Bramswig NC, Nair LD, Myers CT, Dentici ML, Korenke GC, Schoch K, Campeau PM, White SM, Shashi V, Kansagra S, Van Essen AJ, Leuzzi V
Epileptic Disord 2016 Jun 1;18(2):123-36. doi: 10.1684/epd.2016.0830. PMID: 27267311
Tenorio J, Arias P, Martínez-Glez V, Santos F, García-Miñaur S, Nevado J, Lapunzina P
Orphanet J Rare Dis 2014 Sep 20;9:138. doi: 10.1186/s13023-014-0138-0. PMID: 25238977Free PMC Article
Kraoua L, Capri Y, Perrin L, Benmansour A, Verloes A
Am J Med Genet A 2012 Sep;158A(9):2233-8. Epub 2012 Jul 18 doi: 10.1002/ajmg.a.35212. PMID: 22811276

Therapy

Levin MD, Saitta SC, Gripp KW, Wenger TL, Ganesh J, Kalish JM, Epstein MR, Smith R, Czosek RJ, Ware SM, Goldenberg P, Myers A, Chatfield KC, Gillespie MJ, Zackai EH, Lin AE
Am J Med Genet A 2018 Aug;176(8):1711-1722. Epub 2018 Jul 28 doi: 10.1002/ajmg.a.38854. PMID: 30055033Free PMC Article
Mastrangelo M, Scheffer IE, Bramswig NC, Nair LD, Myers CT, Dentici ML, Korenke GC, Schoch K, Campeau PM, White SM, Shashi V, Kansagra S, Van Essen AJ, Leuzzi V
Epileptic Disord 2016 Jun 1;18(2):123-36. doi: 10.1684/epd.2016.0830. PMID: 27267311
Reynaert N, Ockeloen CW, Sävendahl L, Beckers D, Devriendt K, Kleefstra T, Carels CE, Grigelioniene G, Nordgren A, Francois I, de Zegher F, Casteels K
Horm Res Paediatr 2015;83(5):361-4. Epub 2015 Apr 1 doi: 10.1159/000380908. PMID: 25833229
Vlaikou AM, Manolakos E, Noutsopoulos D, Markopoulos G, Liehr T, Vetro A, Ziegler M, Weise A, Kreskowski K, Papoulidis I, Thomaidis L, Syrrou M
Cytogenet Genome Res 2014;142(4):227-38. Epub 2014 Apr 9 doi: 10.1159/000361001. PMID: 24733116
Ornoy A
Reprod Toxicol 2009 Jul;28(1):1-10. Epub 2009 Mar 13 doi: 10.1016/j.reprotox.2009.02.014. PMID: 19490988

Prognosis

Reuter MS, Zech M, Hempel M, Altmüller J, Heung T, Pölsler L, Santer R, Thiele H, Trost B, Kubisch C, Scherer SW, Rudnik-Schöneborn S, Bassett AS, Lessel D
Eur J Hum Genet 2022 May;30(5):611-618. Epub 2022 Mar 18 doi: 10.1038/s41431-022-01077-y. PMID: 35304602Free PMC Article
Chen J, Xia Z, Zhou Y, Ma X, Wang X, Guo Q
BMC Med Genomics 2021 Mar 2;14(1):68. doi: 10.1186/s12920-021-00920-3. PMID: 33653342Free PMC Article
Wong BKY, Sutton VR
Am J Med Genet C Semin Med Genet 2018 Dec;178(4):423-431. Epub 2018 Dec 10 doi: 10.1002/ajmg.c.31658. PMID: 30536540
Liu N, Schoch K, Luo X, Pena LDM, Bhavana VH, Kukolich MK, Stringer S, Powis Z, Radtke K, Mroske C, Deak KL, McDonald MT, McConkie-Rosell A, Markert ML, Kranz PG, Stong N, Need AC, Bick D, Amaral MD, Worthey EA, Levy S; Undiagnosed Diseases Network (UDN), Wangler MF, Bellen HJ, Shashi V, Yamamoto S
Hum Mol Genet 2018 Jul 15;27(14):2454-2465. doi: 10.1093/hmg/ddy146. PMID: 29726930Free PMC Article
Xin B, Puffenberger EG, Turben S, Tan H, Zhou A, Wang H
Proc Natl Acad Sci U S A 2010 Jan 5;107(1):258-63. Epub 2009 Dec 14 doi: 10.1073/pnas.0908457107. PMID: 20018682Free PMC Article

Clinical prediction guides

Choi Y, Choi J, Do H, Hwang S, Seo GH, Choi IH, Keum C, Choi JH, Kang M, Kim GH, Yoo HW, Lee BH
Mol Genet Genomic Med 2023 Apr;11(4):e2127. Epub 2022 Dec 23 doi: 10.1002/mgg3.2127. PMID: 36564961Free PMC Article
Reuter MS, Zech M, Hempel M, Altmüller J, Heung T, Pölsler L, Santer R, Thiele H, Trost B, Kubisch C, Scherer SW, Rudnik-Schöneborn S, Bassett AS, Lessel D
Eur J Hum Genet 2022 May;30(5):611-618. Epub 2022 Mar 18 doi: 10.1038/s41431-022-01077-y. PMID: 35304602Free PMC Article
Mastrangelo M, Scheffer IE, Bramswig NC, Nair LD, Myers CT, Dentici ML, Korenke GC, Schoch K, Campeau PM, White SM, Shashi V, Kansagra S, Van Essen AJ, Leuzzi V
Epileptic Disord 2016 Jun 1;18(2):123-36. doi: 10.1684/epd.2016.0830. PMID: 27267311
Tenorio J, Arias P, Martínez-Glez V, Santos F, García-Miñaur S, Nevado J, Lapunzina P
Orphanet J Rare Dis 2014 Sep 20;9:138. doi: 10.1186/s13023-014-0138-0. PMID: 25238977Free PMC Article
Gropman AL, Duncan WC, Smith AC
Pediatr Neurol 2006 May;34(5):337-50. doi: 10.1016/j.pediatrneurol.2005.08.018. PMID: 16647992

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