2.1 Birth and family history

Born at 9 days post-term of non-consanguineous parents, both health professionals, this firstborn, female infant was noted to have facial anomalies suggestive of a possible genetic syndrome. She was referred by her pediatrician to British Columbia Children's Hospital in Vancouver. Syndromes for which she was genetically tested included Crouzon, Marshall, and Stickler (see Section 2.3 for additional details).

Maternal pregnancy history included two previous, first-trimester miscarriages (one confirmed at about 12 weeks’ gestation and the other suspected, based on menstrual history). There were no maternal pregnancy or prenatal ultrasound concerns with this infant. According to the parents, the baby's birth involved a difficult vaginal forceps delivery requiring episiotomy. There is no family history of genetic disorders although a maternal 12-year-old cousin was born with mild cerebral palsy. This infant's mother was 38 years old and the father was 36. Birth weight was 3004 g (15th percentile), length was 53 cm (90th percentile), and head circumference was 36 cm (75th percentile). According to the parents, the infant failed her initial audiology testing while still in hospital. However, she passed a second test shortly after hospital discharge. The infant was noted to be severely myopic (a characteristic of both Stickler and Marshall syndromes) and has been wearing prescription eyeglasses since early infancy.

At birth, the infant was noted to have a very flat (scooped) nasal bridge and somewhat wide-set eyes (although not hypertelorism), as well as mild proptosis. Her mandible appeared to be normally shaped and placed, neither prognathic (as in Crouzon syndrome) nor micro-gnathic (as in Stickler or Marshall syndromes). Although not measured specifically, her trunk appeared elongated with some shortening of the upper and lower extremities in comparison.

2.2 Developmental neuromotor assessment

At 2.5 months of age, a norm-referenced, developmental assessment was administered: the Harris Infant Neuromotor Test (HINT) (Harris, Megans & Daniels et al., 2010). Reliability and validity have been well established and reported in a number of published articles (Harris, Backman & Mayson et al., 2010; Harris & Daniels, 2001; Tse et al., 2008). Based on the HINT results, the baby was performing at 1 SD from the mean for 2.5-month-old infants (slight motor delay), a finding consistent with the parents' impressions of her motor development. HINT concerns noted included generalized mild/moderate hypotonia, joint hyperextensibility (especially in the upper extremities), and inconsistent head centering in supine. No differences were noted between the right and left upper extremities in muscle tone, active or passive movement. Visual following of a black-and-white picture book was inconsistent and not through an entire horizontal arc, possibly due to the significant myopia. She was a bit immature in the ability to right her head into extension in prone-lying, during passive trunk rotation from supine to prone, and in supported sitting.

In summary, the infant demonstrated slight motor delays, possibly secondary to the generalized hypotonia. Quality of movement was generally normal. What was unusual (and noted also by the infant's mother) was a fairly common tendency to actively position her upper extremities in somewhat of an “arthrogrypotic” posture—shoulders internally rotated, elbows extended, wrists flexed and ulnar-deviated. Although there were no contractures that would suggest arthrogryposis, this is not a typical type of arm posturing in infants. Happily, the infant could move out of this posture and bring hands to midline and to her mouth, as typical at her age.

2.3 Diagnosis and genetic counseling

To rule out Crouzon and Stickler syndromes, the following steps were taken. Crouzon syndrome is caused by pathogenic variants in the fibroblast growth receptors FGFR1, FGFR 2, and FGFR 3. Testing took place at the molecular-genetics laboratory at The Hospital for Sick Children in Toronto and was negative for an FGFR-mediated anomaly. Testing for Marshall syndrome was performed by Connective Tissue Gene Tests, LLC in Allentown, Pennsylvania. All exons of the COL11A1 gene were examined for sequence variations. The DNA sequence revealed an intronic variant at intron 51 in the COL11A1 gene. This particular intronic variation (IVS51+1G>A) is specifically associated with Marshall syndrome but not with Stickler syndrome (Ala-Kokko & Shanske, 2009), thereby ruling out the latter.

Consequently, at 6 months of age, the infant was confirmed to have Marshall syndrome. Because her parents were considering another pregnancy, they were tested to see if either carried the same variant. Because both tested negative for the variant, a genetic counselor estimated that their chance of having a subsequent child with Marshall syndrome was likely <1%. The parents were advised that should the mother become pregnant, they would have the option of pursuing prenatal genetic testing for the COL11A1 gene variant.

2.4 Audiologic assessments

At 8 months of age, the infant received auditory brainstem response testing. Mild hearing loss was noted in the left ear but hearing was within normal limits in the right. Bone conduction testing suggested a sensorineural component to the hearing loss, consistent with findings of three family members with Marshall syndrome in a 2018 study and 17 studies prior to that, as shown in tab. 2 of that article (Bacciu et al., 2018). As these authors concluded: “hearing loss may be considered one of the hallmarks of Marshall syndrome … affecting >80% of patients” (Bacciu et al., 2018, p. e697).

At 4 years of age, mild hearing loss continued on the left but slight hearing loss was now noted on the right. At age 11, she was fitted with a set of Phonak Audeo P50-R hearing aids. At her most recent audiologic assessment at age 12, hearing loss had increased to slight to moderate on the right and mild to moderate on the left. Slowly progressive hearing loss, as experienced by this child, has been reported previously in an adult with Marshall syndrome (Bacciu et al., 2018).

2.5 Ocular assessments

At 1 month of age, she was fitted for spectacles for profound myopia (approximately −19 diopters bilaterally), a finding consistent with a Saudi Arabian study of seven individuals with Marshall syndrome all of whom had high myopia (Khalifa et al., 2014). As of 8 months of age, no other ophthalmological concerns were noted, that is, glaucoma and cataracts. Clinically, she was noted to visually track and follow well and was very socially responsive.

When she was 2.5 years old, a cataract in the right eye was noted, leading to surgery to remove the cataract and replace her right lens. More recently, a cataract was discovered in her left eye but has not been removed because it did not occlude her vision. At her most recent ophthalmology visit (April 2023), everything had remained stable including her prescription for corrective spectacles. Her corrected vision was 20/20 OD (oculus dexter = right eye) and 20/25− OS (oculus sinister = left eye).

2.6 Plastic surgery

In March 2016, nasal reconstructive surgery was employed with a silastic implant. A second surgery took place in October 2022 to replace the previous implant to accommodate her growing face.

2.7 Growth and stature

At age 12.5 years, this child's stature is within normal limits (23rd percentile for age and gender), especially considering that her mother's height is only in the 22nd percentile and her younger brother's (age 8)—who does not have Marshall syndrome—is at the 18th percentile.

2.8 Orthodontic follow-up and treatment

Midface retrusion was shown in four of seven individuals with variants of the COL11A1 gene in a 2020 study from the Czech Republic (Čopíková et al., 2020), as was true also of this young client. Because of this as well as nasal hypoplasia, she has been followed by an orthodontist since the age of 7 years and 9 months, initially with palate expanders and later with a nightly retainer to facilitate upper arch dental alignment and upper jaw forward development. According to her orthodontist: “The objective of interceptive orthodontic treatment at this young age is to relieve the dentition of conditions that would restrict upper jaw growth, and to encourage mid-face development.” At her most recent orthodontic appointment in August 2023, the orthodontist reported: “Positive changes in the upper jaw relationship can be shown as the permanent teeth develop. The effectiveness of this therapy will depend on her tolerance for appliance wear, the pre-pubertal treatment period, and the amount of relative jaw growth.”

4.1 Personal story

This case report arose in part from desires of this child's parents to share the story of their early fears at her initial diagnosis and compare those to how well she has turned out. Although my own goal was to present a longitudinal, clinical description of the child's growth and development—the first of its kind for Marshall syndrome—the parents' goal was to share this “good-news story” with other parents that will or have given birth to children with rare disorders. This perspective is important to share also with pediatric health professionals.

The duration of my pregnancy with my daughter was uneventful; I had no reason to believe that she would be born with any suspected genetic conditions. This is why, at the time of birth, everything seemed so shocking to me. I remember feeling an immediate full-body, all-encompassing dread when the pediatrician explained that there was a problem with my newborn. The only thing that grounded me at that moment was holding her, and realizing that she was content. It was my first experience of motherhood, and although I was confused and panicked about her health, I was consoled by her happiness.

Over the next several weeks, I felt numb. I lacked an appetite and often felt like I was a walking zombie. I avoided my friends and family because I did not know what to say to anyone. Although it was suggested that my daughter had a craniofacial condition, there was no definitive diagnosis. During this time, we were seen by several pediatric specialists, including an audiologist, a neurologist, ophthalmologist, a plastic surgeon, a physiotherapist, and a medical geneticist. At 6 months of age, my daughter was diagnosed with “Marshall syndrome.” It was explained to us that this was a genetic condition that affected collagen production and that the main areas of concern included hearing loss, high myopia, and early-onset arthritis. It was also explained that there were not many cases to glean information from, so I immediately scoured the literature, but to no avail. It was so very hard on me and my husband for the first year of our daughter's life, not knowing how the deficits in her hearing or sight (among others) would affect her life. We made an early decision to keep her out of certain sports for fear of accelerating any arthritis or causing a retinal detachment from contact with her head.

My daughter is now 12 ½ years old and in Grade 7. She has been wearing hearing aids since Grade 6 that are barely noticeable. She wears corrective lenses like so many other children. We abandoned the plan of keeping her out of certain sports; she plays Division 1 soccer and runs track and field, among other sports. She excels at school. She has been an absolute dream.

When I was approached about writing a case report on my daughter, I was more than happy to oblige. I wish I could have found a “good news” case report when my daughter was first born. Retrospectively, those early days did not have to be so traumatic; I did not have to live that first year like a zombie, in fear of the unknown.

When we first met with the medical geneticist, I had endless questions that could not be answered. I wanted to be told that everything would be okay, that my daughter would have a normal life, and that I would have a normal life with her. I will never forget what the geneticist told me that day. Although she could not provide a diagnosis as yet, she recounted what another mother had said about her experience with her child; “You never notice what they can't do because you are too busy noticing what they can do.”

It is so true. I have never noticed anything my daughter could not do. Watching her grow up, I was never disappointed or sad about her condition because I just did not notice it. My life with her has been everything I could have dreamed it to be.

Not surprisingly, the detailed clinical description that precedes this mother's comments supports her conclusions about how well this child is doing now in her preteen years, despite the early diagnosis of Marshall syndrome. Pediatric health professionals, as well as parents of children with this extremely rare disorder, should take heart in these very positive outcomes.