Table 1.
Clinical characteristics of the A, 5 male and B, 6 female patients with arhinia or absent nasal spine (patient No. 8) who underwent detailed phenotyping studies
| A, Evaluation of Males at Initial Diagnosis (Patient No.) | No. 1 | No. 2 | No. 3 | No. 4 | No. 5 | |
|---|---|---|---|---|---|---|
| Age, y | 14.0 | 12.5 | 15.8 | 14.0 | 13.8 | |
| Physical exam | ||||||
| Micropenis | Yes | Yes | Yes | Yes | Yes | |
| Cryptorchidism | No | Yes, b/l | Yes, R | No | Yes, L | |
| Testicular volume, cc | 3 | [Removed at age 4 y] | 2–3 | 1 | 2 | |
| Tanner stage pubic hair | I | – | II | II | II | |
| Endocrine studies | ||||||
| LH, IU/L | < 0.1 | – | <0.1 | <0.15 | <0.1 | |
| FSH, IU/L | < 0.3 | – | <0.3 | <0.5 | <0.3 | |
| Total testosterone, ng/dL | 5.6 | 3.0 | <10.0 | 29.0 | 31.0 | |
| Peak LH (IU/L), GnRH stimulation testa | 1.6 | – | – | 1.5 | – | |
| Peak testosterone (ng/dL), hCG stimulation testb | – | 19 | – | 249 | – | |
| Bone age, y | 12.5 | 12.5 | 13.5 | 13.0 | 14.0 | |
| Hormone therapy (age at initiation, y) | Testosterone (14 y) | Testosterone (12 y) | Testosterone (16 y) | HMG/hCG (16-18); testosterone (14-16; 18) | Testosterone (14 y) | |
| Evaluation as Study Participant | ||||||
| Clinical parameters | ||||||
| Age, y | 25 | 36 | 19 | 28 | 23 | |
| Height, cm | 177.7 | 174.0 | 171.1 | 179.8 | 177.0 | |
| Weight, kg | 90.1 | 92.1 | 97.0 | 114.9 | 91.8 | |
| BMI, kg/m2 | 28.5 | 30.2 | 33.1 | 35.5 | 29.5 | |
| Biochemical studies | ||||||
| LH, IU/L | 0.1 | <0.1 | 0.1 | <0.3 | 0.1 | |
| FSH, IU/L | 0.3 | 0.1 | 0.1 | <0.7 | 0.3 | |
| Total testosterone, ng/dL | 13.0 | 12.0 | 34.6 | 25.0 | 44.0 | |
| Inhibin B, pg/mL | <10.0 | <10.0 | <10.0 | 22.2 | <10.0 | |
| Imaging studies | ||||||
| Brain MRI | ||||||
| Pituitary and hypothalamus | Normal | Normal | Normal | Normal | Pituitary hypoplasia | |
| Olfactory structures | No nerves, bulbs, sulci | No bulbs | No bulbs | No sulcid | No bulbs, tracts | |
| Ophthalmic structures | Hypoplastic | Hypoplastic | Hypoplastic | – | Normal | |
| Internal auditory structures | Normal | Normal | Normal | – | Normal | |
| Testicular volume on ultrasound, R, L, cc | 0.6, 0.7 | c | L 1.1c | – | R 0.4c | |
| Nonreproductive phenotypes | ||||||
| Mirror movements | No | Yes | No | Yes | Yes | |
| Renal agenesis | No | No | No | No | No | |
| Skeletal abnormalities | Hypoplastic ribs (#12) | Hypoplastic ribs (#5, 6, 12) | No | – | No | |
| Dental abnormalities (No. of missing teeth) | Agenesis (2) | 1 ectopic tooth | Agenesis (1) | Normal | Agenesis (3) | |
| Hearing | Normal | Normal | Losse | Losse | Normal | |
| External ears | Small; low-set; no upper pinna | Low-set; protruding; infolded cartilage | Normal | Normal | Normal | |
| Ocular | Normal | Microphthalmia | Anophthalmia | Normal | Normal | |
| Anosmia (UPSIT score) | Yes (8/40) | Yes (6/40) | Yes (12/40) | Yes (–) | Yes (11/40) | |
| Cleft lip/palate (CL/CP) | No | CP | No | CP | CL and CP | |
| SMCHD1 mutation | p.S135N | p.E473G | p.M129R | p.N524S | p.L141F | |
| B, Evaluation of Females at Initial Diagnosis (Patient No.) | No. 6 | No. 7 | No. 8 | No. 9 | No. 10 | No. 11 |
| Age, y | 17.5 | 16.0 | 15.0 | 14.7 | 19.0 | 15.9 |
| Physical exam | ||||||
| Tanner stage, breast | II | II | II | I | I | I |
| Tanner stage, pubic hair | IV | II | II | IV | I | V |
| Endocrine studies | ||||||
| LH (IU/L) | <0.2 | 0.3 | <0.02 | 0.05 | <1.0 | |
| FSH (IU/L) | 0.8 | 1 | <0.09 | 0.7 | <2.0 | |
| Estradiol, pg/mL | 9.7 | 15 | 5 | <1.0 | – | |
| Bone age, y | – | – | 13.5 | 10.0 | – | 13.0 |
| Estrogen replacement, age at initiation, y | None | Yes, 15 | Yes, 15 | Yes, 15 | Yes, 21 | Yes, 16 |
| Evaluation as Study Participant | ||||||
| Clinical parameters | ||||||
| Age, y | 21 | 29 | 19 | 18 | 53 | 23 |
| Height, cm | 161.4 | 169.0 | 182.9 | 169.2 | 165.6 | 165.2 |
| Arm span, cm | 171.8 | 169.0 | 182.0 | 170.0 | 166.3 | – |
| Midparental height, cm | 168.9 | 163.8 | 174.0 | 170.0 | 157.5 | 160.0 |
| Weight, kg | 49.4 | 79.7 | 70.1 | 72.7 | 75.8 | 53.9 |
| BMI, kg/m2 | 19.0 | 27.7 | 21.0 | 25.4 | 27.6 | 21.4 |
| Biochemical studies | ||||||
| LH (IU/L) | <0.1 | <0.1 | 0.1 | <0.1 | 0.2 | <0.3 |
| FSH (IU/L) | 0.4 | 0.3 | 0.1 | <0.1 | 0.5 | <0.7 |
| Estradiol (pg/mL) | <10.0 | <10.0 | <10.0 | <10.0 | <10.0 | – |
| Imaging studies | ||||||
| Brain MRI | ||||||
| Pituitary and hypothalamus | Normal | Normal | Normal | Normal | Normal | Normal |
| Olfactory structures | Hypoplastic sulci, no bulbs | No bulbs | No bulbs | No bulbs | Hypoplastic sulci, no bulbs | d |
| Ophthalmic structures | Hypoplastic orbits | Normal | Thin L optic n. | Normal | Normal | d |
| Internal auditory structures | Normal | Normal | Normal | Normal | Normal | Bulbous deformity R semicircular canal |
| Evaluation as Study Participant | ||||||
| Pelvic ultrasound | ||||||
| R and L ovarian volumes, cc | Not visible | 0.2, 0.4 | 5.5, 3.3 | Not visible | Not visible | – |
| Uterine volume, cc | 1.4 | 3.6 | 21.0 | 12.3 | 15.7 | – |
| Nonreproductive phenotypes | ||||||
| Mirror movements | Yes | No | No | Yes | No | – |
| Renal agenesis | No | No | No | No | No | No |
| Skeletal abnormalities | Clinodactyly, short 4th L MC | Hypoplastic ribs (R; #6, 7) | Hypermobility, arachnodactyly | No | No | Short 4th MCs, hypermobility, leg- and arm-length discrepancy |
| Dental abnormalities (No. of missing teeth) | Agenesis (7) | Normal | Normal | Agenesis (2) | Agenesis (–) | Normal |
| External ears | Normal | Low-set | Normal | Normal | R pinna cupped | Normal |
| Ocular | Anophthalmia | Normal | Normal | Normal | Colobomatous microphthalmia, cataract | Colobomatous microphthalmia, cataract |
| Anosmia (UPSIT score) | Yes (12/40) | Yes (10/40) | Yes (11/40) | Yes (8/40) | Yes (14/30) | Yes (–) |
| Cleft lip/palate | No | No | No | CP | No | CP |
| SMCHD1 mutation | p.N139H | p.E136D | p.M129R | p.G137E | p.H348R | p.N139H |
Although not specifically noted in B, all 6 female patients had normal hearing based on a formal audiologic evaluation. SMCHD1 variants identified by whole-exome sequencing are in bold.
Abbreviations: –, information unavailable; b/l, bilateral; BMI, body mass index; FSH, follicle-stimulating hormone; GnRH, gonadotropin-releasing hormone; R, right; L, left; LH, luteinizing hormone; HMG, human menopausal gonadotropins; hCG, human chorionic gonadotropin; MC, metacarpal; MRI, magnetic resonance imaging; UPSIT, University of Pennsylvania Smell Identification Test.
aGnRH-stimulated LH levels greater than 5 IU/L indicate activation of the neuroreproductive axis (25).
bA peak testosterone level greater than 90 ng/dL after hCG stimulation suggests normal testicular Leydig cell function (26).
cOne or both testicles had been surgically removed.
dRadiologist was unable to comment on olfactory structures because of resolution and motion artifact.
eHistory of recurrent ear infections and myringotomy tubes.